316 results on '"Functional Aspects of Cell Biology"'
Search Results
2. Proteasome inhibition induces microtubule-dependent changes in nuclear morphology
- Author
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Sengupta, Sourabh, Sami, Abdullah Bashar, Gatlin, Jesse C., and Levy, Daniel L.
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- 2025
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Catalog
3. Exosomal miRNA 16-5p/29a-3p from pancreatic cancer induce adipose atrophy by inhibiting adipogenesis and promoting lipolysis.
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Tien, Sui-Chih, Chang, Chin-Chun, Huang, Ching-Hsuan, Peng, Hsuan-Yu, Chang, Yu-Ting, Chang, Ming-Chu, Lee, Wen-Hwa, and Hu, Chun-Mei
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Cell biology ,Functional aspects of cell biology ,Molecular physiology ,Pathophysiology ,Physiology - Abstract
Over 80% of the patients with pancreatic ductal adenocarcinoma (PDAC) have cachexia/wasting syndrome. Cachexia is associated with reduced survival, decreased quality of life, and higher metastasis rates. Here, we demonstrate that fat loss is the earliest feature of PDAC-exosome-induced cachexia. MicroRNA sequencing of exosomal components from normal and cancer-derived exosomes revealed enrichment of miR-16-5p, miR-21-5p, miR-29a-3p, and miR-125b-5p in serum exosomes of mice harboring PDAC and patients with PDAC. Further, miR-16-5p and miR-29a-3p inhibited adipogenesis through decreasing Erlin2 and Cmpk1 expression which downregulates C/EBPβ and PPARγ. Synergistically, miR-29a-3p promotes lipolysis through increasing ATGL expression by suppressing MCT1 expression. Furthermore, PDAC-exosomes deprived of miR-16-5p and miR-29a-3p fail to induce fat loss. Hence, miR-16-5p and miR-29a-3p exosomal miRs are essential for PDAC-induced fat loss. Thus, we unravel that PDAC induces adipose atrophy via exosomal miRs. This knowledge may provide new diagnostic and therapeutic strategies for PDAC-induced cachexia. more...
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- 2024
4. Epidermal growth factor augments the self-renewal capacity of aged hematopoietic stem cells.
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Chang, Vivian, He, Yuwei, Grohe, Samantha, Brady, Morgan, Chan, Aldi, Kadam, Rucha, Fang, Tiancheng, Pang, Amara, Pohl, Katherine, Tran, Evelyn, Li, Michelle, Kan, Jenny, Zhang, Yurun, Lu, Josie, Sasine, Joshua, Himburg, Heather, Yue, Peibin, and Chute, John more...
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Human physiology ,cellular physiology ,functional aspects of cell biology ,molecular medicine ,stem cells research - Abstract
Hematopoietic aging is associated with decreased hematopoietic stem cell (HSC) self-renewal capacity and myeloid skewing. We report that culture of bone marrow (BM) HSCs from aged mice with epidermal growth factor (EGF) suppressed myeloid skewing, increased multipotent colony formation, and increased HSC repopulation in primary and secondary transplantation assays. Mice transplanted with aged, EGF-treated HSCs displayed increased donor cell engraftment within BM HSCs and systemic administration of EGF to aged mice increased HSC self-renewal capacity in primary and secondary transplantation assays. Expression of a dominant negative EGFR in Scl/Tal1+ hematopoietic cells caused increased myeloid skewing and depletion of long term-HSCs in 15-month-old mice. EGF treatment decreased DNA damage in aged HSCs and shifted the transcriptome of aged HSCs from genes regulating cell death to genes involved in HSC self-renewal and DNA repair but had no effect on HSC senescence. These data suggest that EGFR signaling regulates the repopulating capacity of aged HSCs. more...
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- 2024
5. The nuclear transport factor CSE1 drives macronuclear volume increase and macronuclear node coalescence in Stentor coeruleus.
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McGillivary, Rebecca, Sood, Pranidhi, Hammar, Katherine, and Marshall, Wallace
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Biophysics ,Cell biology ,Functional aspects of cell biology - Abstract
Stentor coeruleus provides a unique opportunity to study how cells regulate nuclear shape because its macronucleus undergoes a rapid, dramatic, and developmentally regulated shape change. We found that the volume of the macronucleus increases during coalescence, suggesting an inflation-based mechanism. When the nuclear transport factor, CSE1, is knocked down by RNAi, the shape and volume changes of the macronucleus are attenuated, and nuclear morphology is altered. CSE1 protein undergoes a dynamic relocalization correlated with nuclear shape changes, being mainly cytoplasmic prior to nuclear coalescence, and accumulating inside the macronucleus during coalescence. At the end of regeneration, CSE1 protein levels are reduced as the macronucleus returns to its pre-coalescence volume. We propose a model in which nuclear transport via CSE1 is required to increase the volume of the macronucleus, thereby decreasing the surface-to-volume ratio and driving coalescence of the nodes into a single mass. more...
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- 2023
6. Limiting 20S proteasome assembly leads to unbalanced nucleo-cytoplasmic distribution of 26S/30S proteasomes and chronic proteotoxicity
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Gabriel Ruiz-Romero, María Dolores Berdún, Mark Hochstrasser, Silvia Salas-Pino, and Rafael R. Daga
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Molecular biology ,Organizational aspects of cell biology ,Functional aspects of cell biology ,Science - Abstract
Summary: In addition to the degradation of cell-cycle proteins, short-lived, damaged, or unfolded proteins are constantly cleared from cells by the proteasome. During proliferation, the proteasome localizes to the nucleus and cytoplasm; however, the functional relevance of this compartmentalization remains unclear. Here, we show that folding stress increases 26S/30S proteasome activity, which correlates with the upregulation of Ump1, a chaperone involved in 20S assembly. Conversely, ump1 inactivation results in a drop of 20S and 26S/30S proteasomes. Limited 26S/30S proteasomes in ump1-deficient cells accumulate in the nucleus where they degrade mitotic substrates, allowing cells to proceed through mitosis; however, these cells present cytoplasmic aggregates and constitutive activation of the heat shock response. Thus, our data suggest that an increase in proteasome assembly induced by folding stress functions as an additional layer to proteasome regulation and highlight the importance of balanced proteasome compartmentalization to sustain cell proliferation while maintaining proper cytoplasmic proteostasis. more...
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- 2024
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7. Alternatively spliced MAP4 isoforms have key roles in maintaining microtubule organization and skeletal muscle function
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Lathan Lucas, Larissa Nitschke, Brandon Nguyen, James A. Loehr, George G. Rodney, and Thomas A. Cooper
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Cellular physiology ,Molecular physiology ,Molecular Structure ,Functional aspects of cell biology ,Science - Abstract
Summary: Skeletal muscle cells (myofibers) are elongated non-mitotic, multinucleated syncytia that have adapted a microtubule lattice. Microtubule-associated proteins (MAPs) play roles in regulating microtubule architecture. The most abundant MAP in skeletal muscle is MAP4. MAP4 consists of a ubiquitous MAP4 isoform (uMAP4), expressed in most tissues, and a striated-muscle-specific alternatively spliced isoform (mMAP4) that includes a 3,180-nucleotide exon (exon 8). To determine the role of mMAP4 in skeletal muscle, we generated mice that lack mMAP4 and express only uMAP4 due to genomic deletion of exon 8. We demonstrate that loss of mMAP4 leads to disorganized microtubule architecture and intrinsic loss of force generation. We show that mMAP4 exhibits enhanced association with microtubules compared to uMAP4 and that both the loss of mMAP4 and the concomitant gain of uMAP4 cause loss of muscle function. These results demonstrate the critical role for balanced expression of mMAP4 and uMAP4 for skeletal muscle homeostasis. more...
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- 2024
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8. P16INK4A drives RB1 degradation by UTP14A-catalyzed K810 ubiquitination
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Wenjie Weng, Baozhen Zhang, and Dajun Deng
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Cellular physiology ,Molecular physiology ,Molecular interaction ,Functional aspects of cell biology ,Science - Abstract
Summary: P16INK4A expression is inversely associated with RB1 expression in cancer cells, and P16INK4A inhibits CDK4-catalyzed RB1 phosphorylation. How P16INK4A and RB1 coordinately express and regulate the cell cycle remains to be studied. In the present study, we found that P16INK4A upregulated the E3 ligase UTP14A, which led to the ubiquitination of RB1 at K810 and RB1 degradation. P16INK4A loss consistently disrupted the UTP14A-mediated degradation of RB1 and caused RB1 accumulation. Functionally, P16INK4A loss inhibited RB1 ubiquitination in a cell cycle progression-independent fashion and inhibited proteome-scale ubiquitination in a cell cycle progression-dependent manner. Our findings indicate that there is a negative feedback loop between P16INK4A and RB1 expression and that disruption of this loop may partially rescue the biological outcomes of P16INK4A loss. We also revealed a hitherto unknown function for P16INK4A in regulating proteome-scale ubiquitination by inhibiting cell proliferation, which may be useful for the development of anticancer drugs. more...
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- 2024
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9. Quiescence and aging of melanocyte stem cells and a novel association with programmed death-ligand 1
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Joseph W. Palmer, Kyrene M. Villavicencio, Misgana Idris, Ian J. Baranyk, Nunaya Polycarp, Alex D. Dawson, Dominique Weddle, William J. Pavan, Fabian V. Filipp, and Melissa L. Harris
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Stem cells research ,Functional aspects of cell biology ,Science - Abstract
Summary: Cellular quiescence is a reversible and tightly regulated stem cell function essential for healthy aging. However, the elements that control quiescence during aging remain poorly defined. Using melanocyte stem cells (McSCs), we find that stem cell quiescence is neither passive nor static. For example, gene expression profiling of the transition from proliferating melanoblasts to quiescent melanocyte stem cells reveals tissue-specific regulation of the immune checkpoint protein PD-L1. In vitro, quiescence assays demonstrate that PD-L1 expression is a physiological attribute of quiescence in this cell lineage and reinforces this cell state. In vivo, a subset of quiescent McSCs is marked by PD-L1. While the overall number of McSCs decreases with age, PD-L1+ McSCs appear resistant to depletion. This phenomenon coincides with an aged McSC pool that exhibits a deeper transcriptomic quiescence. We predict that quiescent PD-L1+ stem cells retained with age may serve as cellular targets for reactivation. more...
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- 2024
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10. Defective CFTR modulates mechanosensitive channels TRPV4 and PIEZO1 and drives endothelial barrier failure
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Jean-Pierre Amoakon, Jesun Lee, Pramodha Liyanage, Kavisha Arora, Anja Karlstaedt, Goutham Mylavarapu, Raouf Amin, and Anjaparavanda P. Naren.
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Cell biology ,Functional aspects of cell biology ,Pathophysiology ,Science - Abstract
Summary: Cystic fibrosis (CF) is a genetic disease caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Despite reports of CFTR expression on endothelial cells, pulmonary vascular perturbations, and perfusion deficits in CF patients, the mechanism of pulmonary vascular disease in CF remains unclear. Here, our pilot study of 40 CF patients reveals a loss of small pulmonary blood vessels in patients with severe lung disease. Using a vessel-on-a-chip model, we establish a shear-stress-dependent mechanism of endothelial barrier failure in CF involving TRPV4, a mechanosensitive channel. Furthermore, we demonstrate that CFTR deficiency downregulates the function of PIEZO1, another mechanosensitive channel involved in angiogenesis and wound repair, and exacerbates loss of small pulmonary blood vessel. We also show that CFTR directly interacts with PIEZO1 and enhances its function. Our study identifies key cellular targets to mitigate loss of small pulmonary blood vessels in CF. more...
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- 2024
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11. Activation of limbal epithelial proliferation is partly controlled by the ACE2-LCN2 pathway
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Huimin Jiang, Min Liu, Wending Yang, Yi-Kai Hong, Dan Xu, Elif Kayaalp Nalbant, Elwin D. Clutter, Parisa Foroozandeh, Nihal Kaplan, Jan Wysocki, Daniel Batlle, Stephen D. Miller, Kurt Lu, and Han Peng more...
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Molecular medicine ,Stem cells research ,Functional aspects of cell biology ,Science - Abstract
Summary: In response to corneal injury, an activation of corneal epithelial stem cells and their direct progeny the early transit amplifying (eTA) cells to rapidly proliferate is critical for proper re-epithelialization. Thus, it is important to understand how such stem/eTA cell activation is regulated. Angiotensin-converting enzyme 2 (ACE2) is predominantly expressed in the stem/eTA-enriched limbal epithelium but its role in the limbal epithelium was unclear. Single cell RNA sequencing (scRNA-seq) suggested that Ace2 involved the proliferation of the stem/eTA cells. Ace2 was reduced following corneal injury. Such reduction enhanced limbal epithelial proliferation and downregulated LCN2, a negative regulator of proliferation in a variety of tissues, via upregulating TGFA and consequently activating epidermal growth factor receptor (EGFR). Inhibition of EGFR or overexpression of LCN2 reversed the increased proliferation in limbal epithelial cells lacking ACE2. Our findings demonstrate that after corneal injury, ACE2 is downregulated, which activates limbal epithelial cell proliferation via a TGFA/EGFR/LCN2 pathway. more...
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- 2024
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12. Fission yeast Bgs1 glucan synthase participates in the control of growth polarity and membrane traffic
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Mariona Ramos, Rebeca Martín-García, M. Ángeles Curto, Laura Gómez-Delgado, M. Belén Moreno, Mamiko Sato, Elvira Portales, Masako Osumi, Sergio A. Rincón, Pilar Pérez, Juan C. Ribas, and Juan C.G. Cortés more...
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Functional aspects of cell biology ,Mycology ,Organizational aspects of cell biology ,Science - Abstract
Summary: Rod-shaped fission yeast grows through cell wall expansion at poles and septum, synthesized by essential glucan synthases. Bgs1 synthesizes the linear β(1,3)glucan of primary septum at cytokinesis. Linear β(1,3)glucan is also present in the wall poles, suggesting additional Bgs1 roles in growth polarity. Our study reveals an essential collaboration between Bgs1 and Tea1-Tea4, but not other polarity factors, in controlling growth polarity. Simultaneous absence of Bgs1 function and Tea1-Tea4 causes complete loss of growth polarity, spread of other glucan synthases, and spherical cell formation, indicating this defect is specifically due to linear β(1,3)glucan absence. Furthermore, linear β(1,3)glucan absence induces actin patches delocalization and sterols spread, which are ultimately responsible for the growth polarity loss without Tea1-Tea4. This suggests strong similarities in Bgs1 functions controlling actin structures during cytokinesis and polarized growth. Collectively, our findings unveil that cell wall β(1,3)glucan regulates polarized growth, like the equivalent extracellular matrix in neuronal cells. more...
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- 2024
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13. Epidermal growth factor augments the self-renewal capacity of aged hematopoietic stem cells
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Vivian Y. Chang, Yuwei He, Samantha Grohe, Morgan R. Brady, Aldi Chan, Rucha S. Kadam, Tiancheng Fang, Amara Pang, Katherine Pohl, Evelyn Tran, Michelle Li, Jenny Kan, Yurun Zhang, Josie J. Lu, Joshua P. Sasine, Heather A. Himburg, Peibin Yue, and John P. Chute more...
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Human physiology ,cellular physiology ,molecular medicine ,stem cells research ,functional aspects of cell biology ,Science - Abstract
Summary: Hematopoietic aging is associated with decreased hematopoietic stem cell (HSC) self-renewal capacity and myeloid skewing. We report that culture of bone marrow (BM) HSCs from aged mice with epidermal growth factor (EGF) suppressed myeloid skewing, increased multipotent colony formation, and increased HSC repopulation in primary and secondary transplantation assays. Mice transplanted with aged, EGF-treated HSCs displayed increased donor cell engraftment within BM HSCs and systemic administration of EGF to aged mice increased HSC self-renewal capacity in primary and secondary transplantation assays. Expression of a dominant negative EGFR in Scl/Tal1+ hematopoietic cells caused increased myeloid skewing and depletion of long term-HSCs in 15-month-old mice. EGF treatment decreased DNA damage in aged HSCs and shifted the transcriptome of aged HSCs from genes regulating cell death to genes involved in HSC self-renewal and DNA repair but had no effect on HSC senescence. These data suggest that EGFR signaling regulates the repopulating capacity of aged HSCs. more...
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- 2024
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14. The HRD1-SEL1L ubiquitin ligase regulates stress granule homeostasis in couple with distinctive signaling branches of ER stress
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Wenbo Shi, Ran Ding, Yilin Chen, Fubo Ji, Junfang Ji, Weirui Ma, and Jianping Jin
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Cell biology ,Cellular physiology ,Functional aspects of cell biology ,Science - Abstract
Summary: Stress granules (SGs) are membrane-less cellular compartments which are dynamically assembled via biomolecular condensation mechanism when eukaryotic cells encounter environmental stresses. SGs are important for gene expression and cell fate regulation. Dysregulation of SG homeostasis has been linked to human neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we report that the HRD1-SEL1L ubiquitin ligase complex specifically regulates the homeostasis of heat shock-induced SGs through the ubiquitin-proteasome system (UPS) and the UPS-associated ATPase p97. Mechanistically, the HRD1-SEL1L complex mediates SG homeostasis through the BiP-coupled PERK-eIF2α signaling axis of endoplasmic reticulum (ER) stress, thereby coordinating the unfolded protein response (UPR) with SG dynamics. Furthermore, we show that the distinctive branches of ER stress play differential roles in SG homeostasis. Our study indicates that the UPS and the UPR together via the HRD1-SEL1L ubiquitin ligase to maintain SG homeostasis in a stressor-dependent manner. more...
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- 2024
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15. A novel NF2 splicing mutant causes neurofibromatosis type 2 via liquid-liquid phase separation with large tumor suppressor and Hippo pathway
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Jia, Zexiao, Yang, Shuxu, Li, Mengyao, Lei, Zhaoying, Ding, Xue, Fan, Mingjie, Wang, Dixian, Xie, Dajiang, Zhou, Hui, Qiu, Yue, Zhuang, Qianqian, Li, Dan, Yang, Wei, Qi, Xuchen, Cang, Xiaohui, Zhao, Jing-Wei, Wang, Wenqi, Lin, Aifu, and Yan, Qingfeng more...
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Biochemistry and Cell Biology ,Biological Sciences ,Neurofibromatosis ,Cancer ,Pediatric ,Neurosciences ,Genetics ,Rare Diseases ,Aetiology ,2.1 Biological and endogenous factors ,Clinical genetics ,Functional aspects of cell biology ,Pathophysiology - Abstract
Neurofibromatosis type 2 is an autosomal dominant multiple neoplasia syndrome and is usually caused by mutations in the neurofibromin 2 (NF2) gene, which encodes a tumor suppressor and initiates the Hippo pathway. However, the mechanism by which NF2 functions in the Hippo pathway isn't fully understood. Here we identified a NF2 c.770-784del mutation from a neurofibromatosis type 2 family. MD simulations showed that this mutation significantly changed the structure of the F3 module of the NF2-FERM domain. Functional assays indicated that the NF2 c.770-784del variant formed LLPS in the cytoplasm with LATS to restrain LATS plasma membrane localization and inactivated the Hippo pathway. Besides, this deletion partly caused a skipping of exon 8 and reduced the protein level of NF2, collectively promoting proliferation and tumorigenesis of meningeal cells. We identified an unrecognized mechanism of LLPS and splicing skipping for the NF2-induced Hippo pathway, which provided new insight into the pathogenesis of neurofibromatosis type 2. more...
- Published
- 2022
16. Propagation dynamics of electrotactic motility in large epithelial cell sheets
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Zhang, Yan, Xu, Guoqing, Wu, Jiandong, Lee, Rachel M, Zhu, Zijie, Sun, Yaohui, Zhu, Kan, Losert, Wolfgang, Liao, Simon, Zhang, Gong, Pan, Tingrui, Xu, Zhengping, Lin, Francis, and Zhao, Min
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Biochemistry and Cell Biology ,Engineering ,Biological Sciences ,Biomedical Engineering ,Bioengineering ,Biological sciences ,Cell biology ,Functional aspects of cell biology ,Systems biology - Abstract
Directional migration initiated at the wound edge leads epithelia to migrate in wound healing. How such coherent migration is achieved is not well understood. Here, we used electric fields to induce robust migration of sheets of human keratinocytes and developed an in silico model to characterize initiation and propagation of epithelial collective migration. Electric fields initiate an increase in migration directionality and speed at the leading edge. The increases propagate across the epithelial sheets, resulting in directional migration of cell sheets as coherent units. Both the experimental and in silico models demonstrated vector-like integration of the electric and default directional cues at free edge in space and time. The resultant collective migration is consistent in experiments and modeling, both qualitatively and quantitatively. The keratinocyte model thus faithfully reflects key features of epithelial migration as a coherent tissue in vivo, e.g. that leading cells lead, and that epithelium maintains cell-cell junction. more...
- Published
- 2022
17. Histone H2A ubiquitination resulting from Brap loss of function connects multiple aging hallmarks and accelerates neurodegeneration
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Guo, Yan, Chomiak, Alison A, Hong, Ye, Lowe, Clara C, Kopsidas, Caroline A, Chan, Wen-Ching, Andrade, Jorge, Pan, Hongna, Zhou, Xiaoming, Monuki, Edwin S, and Feng, Yuanyi
- Subjects
Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Biological Sciences ,Brain Disorders ,Alzheimer's Disease ,Human Genome ,Aging ,Acquired Cognitive Impairment ,Neurodegenerative ,Dementia ,Stem Cell Research ,Stem Cell Research - Nonembryonic - Non-Human ,Neurosciences ,Genetics ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Aetiology ,1.1 Normal biological development and functioning ,Underpinning research ,2.1 Biological and endogenous factors ,Generic health relevance ,Biological sciences ,Cell biology ,Cellular neuroscience ,Functional aspects of cell biology ,Neuroscience ,Genome Instability ,cellular senescence ,histone ubiquitination ,Proteostasis ,neuroinflammation ,neurodegeneration - Abstract
Aging is an intricate process characterized by multiple hallmarks including stem cell exhaustion, genome instability, epigenome alteration, impaired proteostasis, and cellular senescence. Whereas each of these traits is detrimental at the cellular level, it remains unclear how they are interconnected to cause systemic organ deterioration. Here we show that abrogating Brap, a BRCA1-associated protein essential for neurogenesis, results in persistent DNA double-strand breaks and elevation of histone H2A mono- and poly-ubiquitination (H2Aub). These defects extend to cellular senescence and proteasome-mediated histone H2A proteolysis with alterations in cells' proteomic and epigenetic states. Brap deletion in the mouse brain causes neuroinflammation, impaired proteostasis, accelerated neurodegeneration, and substantially shortened the lifespan. We further show the elevation of H2Aub also occurs in human brain tissues with Alzheimer's disease. These data together suggest that chromatin aberrations mediated by H2Aub may act as a nexus of multiple aging hallmarks and promote tissue-wide degeneration. more...
- Published
- 2022
18. Dry molten globule conformational state of CYP11A1 (SCC) regulates the first step of steroidogenesis in the mitochondrial matrix
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Himangshu S. Bose
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functional aspects of cell biology ,properties of biomolecules ,protein folding ,Science - Abstract
Summary: Multiple metabolic events occur in mitochondria. Mitochondrial protein translocation from the cytoplasm across compartments depends on the amino acid sequence within the precursor. At the mitochondria associated-ER membrane, misfolding of a mitochondrial targeted protein prior to import ablates metabolism. CYP11A1, cytochrome P450 cholesterol side chain cleavage enzyme (SCC), is imported from the cytoplasm to mitochondrial matrix catalyzing cholesterol to pregnenolone, an essential step for metabolic processes and mammalian survival. Multiple steps regulate the availability of an actively folded SCC; however, the mechanism is unknown. We identified that a dry molten globule state of SCC exists in the matrix by capturing intermediate protein folding steps dictated by its C-terminus. The intermediate dry molten globule state in the mitochondrial matrix of living cells is stable with a limited network of interaction and is inactive. The dry molten globule is activated with hydrogen ions availability, triggering cleavage of cholesterol sidechain, and initiating steroidogenesis. more...
- Published
- 2024
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19. USP7 upregulated by TGF-β1 promotes ferroptosis via inhibiting LATS1-YAP axis in sepsis-induced acute lung injury
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Hong Lv, Jing Yu, Xingjia Qian, Jun Shu, Qiuhong Qian, Luhong Shen, Dongfang Shi, Zhengzheng Tao, Guiqin Fan, Bufeng Zhuang, and Bing Lu
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Pathophysiology ,Cell biology ,Functional aspects of cell biology ,Science - Abstract
Summary: Our work aimed to investigate the interactive roles of transforming growth factor β1 (TGF-β1), ubiquitin-specific-processing protease 7 (USP7), and Yes-associated protein (YAP) in ferroptosis during sepsis-secondary acute lung injury (ALI). Our study demonstrated that ferroptosis was aggravated by TGF-β1 in both cellular and animal models of acute lung injury. Additionally, YAP upregulated glutathione peroxidase 4 (GPX4) and SLC7A11 by regulating the binding of TEAD4 to GPX4/SLC7A11 promoters. Furthermore, large tumor suppressor kinase 1 (LATS1) knockdown resulted in YAP expression stimulation, while USP7 downregulated YAP via deubiquitinating and stabilizing LATS1/2. YAP overexpression or USP7/LATS1 silencing reduced ferroptosis process, which regulated YAP through a feedback loop. However, TGF-β1 annulled the repression of ferroptosis by YAP overexpression or LATS1/USP7 knockdown. By elucidating the molecular interactions between TGF-β1, USP7, LATS1/2, and YAP, we identified a new regulatory axis of ferroptosis in sepsis-secondary ALI. Our study sheds light on the pathophysiology of ferroptosis and proposes a potential therapeutic approach for sepsis-induced ALI. more...
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- 2024
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20. Enhanced and sustained T cell activation in response to fluid shear stress
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Nicole S. Sarna, Shanay H. Desai, Benjamin G. Kaufman, Natalie M. Curry, Anne M. Hanna, and Michael R. King
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Molecular physiology ,Components of the immune system ,Specialized functions of cells ,Functional aspects of cell biology ,Science - Abstract
Summary: The efficacy of T cell therapies in treating solid tumors is limited by poor in vivo persistence, proliferation, and cytotoxicity, which can be attributed to limited and variable ex vivo activation. Herein, we present a 10-day kinetic profile of T cells subjected to fluid shear stress (FSS) ex vivo, with and without stimulation utilizing bead-conjugated anti-CD3/CD28 antibodies. We demonstrate that mechanical stimulation via FSS combined with bead-bound anti-CD3/CD28 antibodies yields a synergistic effect, resulting in amplified and sustained downstream signaling (NF-κB, c-Fos, and NFAT), expression of activation markers (CD69 and CD25), proliferation and production of pro-inflammatory cytokines (IFN-γ, TNF-α, and IL-2). This study represents the first characterization of the dynamic response of primary T cells to FSS. Collectively, our findings underscore the critical role of mechanosensitive ion channel-mediated mechanobiological signaling in T cell activation and fitness, enabling the development of strategies to address the current challenges associated with poor immunotherapy outcomes. more...
- Published
- 2024
- Full Text
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21. RSU-1 regulates the integrity of dense bodies in muscle cells of aging Caenorhabditis elegans
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Ling Jiang, Xinyan Wang, Dandan Zhang, Karen Wing Yee Yuen, and Yu Chung Tse
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molecular physiology ,molecular mechanism of behavior ,Specialized functions of cells ,Functional aspects of cell biology ,Science - Abstract
Summary: Muscle contraction is vital for animal survival, and the sarcomere is the fundamental unit for this process. However, the functions of many conserved sarcomere proteins remain unknown, as their mutants do not exhibit obvious defects. To address this, Caenorhabditis elegans was utilized as a model organism to investigate RSU-1 function in the body wall muscle. RSU-1 is found to colocalize with UNC-97 at the dense body and M-line, and it is particularly crucial for regulating locomotion in aging worms, rather than in young worms. This suggests that RSU-1 has a specific function in maintaining muscle function during aging. Furthermore, the interaction between RSU-1 and UNC-97/PINCH is essential for RSU-1 to modulate locomotion, preserve filament structure, and sustain the M-line and dense body throughout aging. Overall, these findings highlight the significant contribution of RSU-1, through its interaction with UNC-97, in maintaining proper muscle cell function in aging worms. more...
- Published
- 2024
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22. VDAC1-interacting molecules promote cell death in cancer organoids through mitochondrial-dependent metabolic interference
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Stefano Conti Nibali, Silvia De Siervi, Enrico Luchinat, Andrea Magrì, Angela Messina, Lorenza Brocca, Stefania Mantovani, Barbara Oliviero, Mario U. Mondelli, Vito De Pinto, Cristian Turato, Cristina Arrigoni, and Marco Lolicato more...
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Small molecule ,Molecular medicine ,Functional aspects of cell biology ,Science - Abstract
Summary: The voltage-dependent anion-selective channel isoform 1 (VDAC1) is a pivotal component in cellular metabolism and apoptosis with a prominent role in many cancer types, offering a unique therapeutic intervention point. Through an in-silico-to-in-vitro approach we identified a set of VA molecules (VDAC Antagonists) that selectively bind to VDAC1 and display specificity toward cancer cells. Biochemical characterization showed that VA molecules can directly interact with VDAC1 with micromolar affinity by competing with the endogenous ligand NADH for a partially shared binding site. NADH displacement results in mitochondrial distress and reduced cell proliferation, especially when compared to non-cancerous cells. Experiments performed on organoids derived from intrahepatic cholangiocarcinoma patients demonstrated a dose-dependent reduction in cell viability upon treatment with VA molecules with lower impact on healthy cells than conventional treatments like gemcitabine. VA molecules are chemical entities representing promising candidates for further optimization and development as cancer therapy strategies through precise metabolic interventions. more...
- Published
- 2024
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23. Mitochondrial F0F1-ATP synthase governs the induction of mitochondrial fission
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Charlène Lhuissier, Valérie Desquiret-Dumas, Anaïs Girona, Jennifer Alban, Justine Faure, Julien Cassereau, Philippe Codron, Guy Lenaers, Olivier R. Baris, Naïg Gueguen, and Arnaud Chevrollier
- Subjects
Biochemistry ,Cell biology ,Functional aspects of cell biology ,Science - Abstract
Summary: Mitochondrial dynamics is a process that balances fusion and fission events, the latter providing a mechanism for segregating dysfunctional mitochondria. Fission is controlled by the mitochondrial membrane potential (ΔΨm), optic atrophy 1 (OPA1) cleavage, and DRP1 recruitment. It is thought that this process is closely linked to the activity of the mitochondrial respiratory chain (MRC). However, we report here that MRC inhibition does not decrease ΔΨm nor increase fission, as evidenced by hyperconnected mitochondria. Conversely, blocking F0F1-ATP synthase activity induces fragmentation. We show that the F0F1-ATP synthase is sensing the inhibition of MRC activity by immediately promoting its reverse mode of action to hydrolyze matrix ATP and restoring ΔΨm, thus preventing fission. While this reverse mode is expected to be inhibited by the ATPase inhibitor ATPIF1, we show that this sensing is independent of this factor. We have unraveled an unexpected role of F0F1-ATP synthase in controlling the induction of fission by sensing and maintaining ΔΨm. more...
- Published
- 2024
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24. Glucose starvation causes ferroptosis-mediated lysosomal dysfunction
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Kenji Miki, Mikako Yagi, Dongchon Kang, Yuya Kunisaki, Koji Yoshimoto, and Takeshi Uchiumi
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Cellular physiology ,Cell biology ,Functional aspects of cell biology ,Science - Abstract
Summary: Lysosomes, the hub of metabolic signaling, are associated with various diseases and participate in autophagy by supplying nutrients to cells under nutrient starvation. However, their function and regulation under glucose starvation remain unclear and are studied herein. Under glucose starvation, lysosomal protein expression decreased, leading to the accumulation of damaged lysosomes. Subsequently, cell death occurred via ferroptosis and iron accumulation due to DMT1 degradation. GPX4, a key factor in ferroptosis inhibition located on the outer membrane of lysosomes, accumulated in lysosomes, especially under glucose starvation, to protect cells from ferroptosis. ALDOA, GAPDH, NAMPT, and PGK1 are also located on the outer membrane of lysosomes and participate in lysosomal function. These enzymes did not function effectively under glucose starvation, leading to lysosomal dysfunction and ferroptosis. These findings may facilitate the treatment of lysosomal-related diseases. more...
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- 2024
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25. Tumor-derived extracellular vesicles as a biomarker for breast cancer diagnosis and metastasis monitoring
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Feng Xu, Ke Wang, Chengjun Zhu, Lingling Fan, Ye Zhu, Jacqueline F. Wang, Xintong Li, Yiqiu Liu, Yuhan Zhao, Chuandong Zhu, Wenwen Zhang, Fang Yang, Jian Xu, Zhe Li, and Xiaoxiang Guan
- Subjects
Oncology ,Functional aspects of cell biology ,Science - Abstract
Summary: It is imperative to explore biomarkers that are both precise and readily accessible in the comprehensive management of breast cancer. A multicenter cohort, including 512 breast cancer patients and 198 nonneoplastic individuals, was recruited to detect the level of tumor-derived extracellular vesicles using our method based on dual DNA tetrahedral nanostructures. The level of tumor-derived extracellular vesicles was significantly higher in newly diagnosed breast cancer patients than in nonneoplastic individuals at a cutoff value of 3.58 U/μL. For postoperative metastasis monitoring, the level of tumor-derived extracellular vesicles was significantly higher in breast cancer patients with metastasis than in those without metastasis at a cutoff value of 3.91 U/μL. Its efficacy of diagnosis and metastasis monitoring was superior to traditional tumor markers. Elevated level of tumor-derived extracellular vesicles served as a predictive biomarker for diagnosis and metastasis monitoring in breast cancer patients. more...
- Published
- 2024
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26. Cell non-autonomous control of autophagy and metabolism by glial cells
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Melissa G. Metcalf, Samira Monshietehadi, Arushi Sahay, Jenni Durieux, Ashley E. Frakes, Martina Velichkovska, Cesar Mena, Amelia Farinas, Melissa Sanchez, and Andrew Dillin
- Subjects
Biological sciences ,Neuroscience ,Cell biology ,Functional aspects of cell biology ,Science - Abstract
Summary: Glia are the protectors of the nervous system, providing neurons with support and protection from cytotoxic insults. We previously discovered that four astrocyte-like glia can regulate organismal proteostasis and longevity in C. elegans. Expression of the UPRER transcription factor, XBP-1s, in these glia increases stress resistance, and longevity, and activates the UPRER in intestinal cells via neuropeptides. Autophagy, a key regulator of metabolism and aging, has been described as a cell autonomous process. Surprisingly, we find that glial XBP-1s enhances proteostasis and longevity by cell non-autonomously reprogramming organismal lipid metabolism and activating autophagy. Glial XBP-1s regulates the activation of another transcription factor, HLH-30/TFEB, in the intestine. HLH-30 activates intestinal autophagy, increases intestinal lipid catabolism, and upregulates a robust transcriptional program. Our study reveals a novel role for glia in regulating peripheral lipid metabolism, autophagy, and organellar health through peripheral activation of HLH-30 and autophagy. more...
- Published
- 2024
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27. Deciphering cellular signals in adult mouse sinoatrial node cells
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Reddy, Gopireddy R, Ren, Lu, Thai, Phung N, Caldwell, Jessica L, Zaccolo, Manuela, Bossuyt, Julie, Ripplinger, Crystal M, Xiang, Yang K, Nieves-Cintrón, Madeline, Chiamvimonvat, Nipavan, and Navedo, Manuel F more...
- Subjects
Biochemistry and Cell Biology ,Medical Physiology ,Biomedical and Clinical Sciences ,Biological Sciences ,Heart Disease ,Cardiovascular ,Aetiology ,2.1 Biological and endogenous factors ,Biology experimental methods ,Cell biology ,Functional aspects of cell biology ,biosensors ,FRET ,cAMP ,cardiac cells ,signal transduction ,heart failure - Abstract
Sinoatrial node (SAN) cells are the pacemakers of the heart. This study describes a method for culturing and infection of adult mouse SAN cells with FRET-based biosensors that can be exploited to examine signaling events. SAN cells cultured in media with blebbistatin or (S)-nitro-blebbistatin retain their morphology, protein distribution, action potential (AP) waveform, and cAMP dynamics for at least 40 h. SAN cells expressing targeted cAMP sensors show distinct β-adrenergic-mediated cAMP pools. Cyclic GMP, protein kinase A, Ca2+/CaM kinase II, and protein kinase D in SAN cells also show unique dynamics to different stimuli. Heart failure SAN cells show a decrease in cAMP and cGMP levels. In summary, a reliable method for maintaining adult mouse SAN cells in culture is presented, which facilitates studies of signaling networks and regulatory mechanisms during physiological and pathological conditions. more...
- Published
- 2022
28. Electrically synchronizing and modulating the dynamics of ERK activation to regulate cell fate
- Author
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Guo, Liang, Zhu, Kan, Pargett, Michael, Contreras, Adam, Tsai, Patrick, Qing, Quan, Losert, Wolfgang, Albeck, John, and Zhao, Min
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Biotechnology ,Cell biology ,Functional aspects of cell biology ,Integrative aspects of cell biology - Abstract
Intracellular signaling dynamics play fundamental roles in cell biology. Precise modulation of the amplitude, duration, and frequency of signaling activation will be a powerful approach to investigate molecular mechanisms as well as to engineer signaling to control cell behaviors. Here, we showed a practical approach to achieve precise amplitude modulation (AM), frequency modulation (FM), and duration modulation (DM) of MAP kinase activation. Alternating current (AC) electrical stimulation induced synchronized ERK activation. Amplitude and duration of ERK activation were controlled by varying stimulation strength and duration. ERK activation frequencies were arbitrarily modulated with trains of short AC applications with accurately defined intervals. Significantly, ERK dynamics coded by well-designed AC can rewire PC12 cell fate independent of growth factors. This technique can be used to synchronize and modulate ERK activation dynamics, thus would offer a practical way to control cell behaviors in vivo without the use of biochemical agents or genetic manipulation. more...
- Published
- 2021
29. RACK1 promotes Shigella flexneri actin-mediated invasion, motility, and cell-to-cell spreading
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Karla N. Valenzuela-Valderas, Elmira Farrashzadeh, Yuen-Yan Chang, Yunnuo Shi, Renee Raudonis, Brendan M. Leung, John R. Rohde, Jost Enninga, and Zhenyu Cheng
- Subjects
Cellular physiology ,Bacteriology ,Functional aspects of cell biology ,Science - Abstract
Summary: Shigella flexneri is an intracellular bacterium that hijacks the host actin cytoskeleton to invade and disseminate within the colonic epithelium. Shigella’s virulence factors induce actin polymerization, leading to bacterial uptake, actin tail formation, actin-mediated motility, and cell-to-cell spreading. Many host factors involved in the Shigella-prompted actin rearrangements remain elusive. Here, we studied the role of a host protein receptor for activated C kinase 1 (RACK1) in actin cytoskeleton dynamics and Shigella infection. We used time-lapse imaging to demonstrate that RACK1 facilitates Shigella-induced actin cytoskeleton remodeling at multiple levels during infection of epithelial cells. Silencing RACK1 expression impaired Shigella-induced rapid polymerizing structures, reducing host cell invasion, bacterial motility, and cell-to-cell spreading. In uninfected cells, RACK1 silencing reduced jasplakinolide-mediated filamentous actin aggregate formation and negatively affected actin turnover in fast polymerizing structures, such as membrane ruffles. Our findings provide a role of RACK1 in actin cytoskeleton dynamics and Shigella infection. more...
- Published
- 2023
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30. OGT/HIF-2α axis promotes the progression of clear cell renal cell carcinoma and regulates its sensitivity to ferroptosis
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Zhou Yang, Xiyi Wei, Chengjian Ji, Xiaohan Ren, Wei Su, Yichun Wang, Jingwan Zhou, Zheng Zhao, Pengcheng Zhou, Kejie Zhao, Bing Yao, Ninghong Song, and Chao Qin
- Subjects
Molecular biology experimental approach ,Molecular network ,In vitro toxicology ,Functional aspects of cell biology ,Cancer ,Science - Abstract
Summary: O-GlcNAc transferase (OGT) acts in the development of various cancers, but its role in clear cell renal cell carcinoma (ccRCC) remains unclear. In this study, we found that OGT was upregulated in ccRCC and this upregulation was associated with a worse survival. Moreover, OGT promoted the proliferation, clone formation, and invasion of VHL-mutated ccRCC cells. Mechanistically, OGT increased the protein level of hypoxia-inducible factor-2α (HIF-2α) (the main driver of the clear cell phenotype) by repressing ubiquitin‒proteasome system-mediated degradation. Interestingly, the OGT/HIF-2α axis conferred ccRCC a high sensitivity to ferroptosis. In conclusion, OGT promotes the progression of VHL-mutated ccRCC by inhibiting the degradation of HIF-2α, and agents that can modulate the OGT/HIF-2α axis may exert therapeutic effects on mutated VHL ccRCC. more...
- Published
- 2023
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31. Sequence-directed concentration of G protein-coupled receptors in COPII vesicles
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Xin Xu, Nevin A. Lambert, and Guangyu Wu
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Cell biology ,Integrative aspects of cell biology ,Functional aspects of cell biology ,Science - Abstract
Summary: G protein-coupled receptors (GPCRs) constitute the largest superfamily of plasma membrane signaling proteins. However, virtually nothing is known about their recruitment to COPII vesicles for forward delivery after synthesis in the endoplasmic reticulum (ER). Here, we demonstrate that some GPCRs are highly concentrated at ER exit sites (ERES) before COPII budding. Angiotensin II type 2 receptor (AT2R) and CXCR4 concentration are directed by a di-acidic motif and a 9-residue domain, respectively, and these motifs also control receptor ER-Golgi traffic. We further show that AT2R interacts with Sar1 GTPase and that distinct GPCRs have different ER-Golgi transport rates via COPII which is independent of their concentration at ERES. Collectively, these data demonstrate that GPCRs can be actively captured by COPII via specific motifs and direct interaction with COPII components that in turn affects their export dynamics, and provide important insights into COPII targeting and forward trafficking of nascent GPCRs. more...
- Published
- 2023
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32. A quinolin-8-ol sub-millimolar inhibitor of UGGT, the ER glycoprotein folding quality control checkpoint
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Kevin P. Guay, Roberta Ibba, J.L. Kiappes, Snežana Vasiljević, Francesco Bonì, Maria De Benedictis, Ilaria Zeni, James D. Le Cornu, Mario Hensen, Anu V. Chandran, Anastassia L. Kantsadi, Alessandro T. Caputo, Juan I. Blanco Capurro, Yusupha Bayo, Johan C. Hill, Kieran Hudson, Andrea Lia, Juliane Brun, Stephen G. Withers, Marcelo Martí, Emiliano Biasini, Angelo Santino, Matteo De Rosa, Mario Milani, Carlos P. Modenutti, Daniel N. Hebert, Nicole Zitzmann, and Pietro Roversi more...
- Subjects
Chemistry ,Cell biology ,Functional aspects of cell biology ,Science - Abstract
Summary: Misfolded glycoprotein recognition and endoplasmic reticulum (ER) retention are mediated by the ER glycoprotein folding quality control (ERQC) checkpoint enzyme, UDP-glucose glycoprotein glucosyltransferase (UGGT). UGGT modulation is a promising strategy for broad-spectrum antivirals, rescue-of-secretion therapy in rare disease caused by responsive mutations in glycoprotein genes, and many cancers, but to date no selective UGGT inhibitors are known. The small molecule 5-[(morpholin-4-yl)methyl]quinolin-8-ol (5M-8OH-Q) binds a CtUGGTGT24 “WY” conserved surface motif conserved across UGGTs but not present in other GT24 family glycosyltransferases. 5M-8OH-Q has a 47 μM binding affinity for CtUGGTGT24 in vitro as measured by ligand-enhanced fluorescence. In cellula, 5M-8OH-Q inhibits both human UGGT isoforms at concentrations higher than 750 μM. 5M-8OH-Q binding to CtUGGTGT24 appears to be mutually exclusive to M5-9 glycan binding in an in vitro competition experiment. A medicinal program based on 5M-8OH-Q will yield the next generation of UGGT inhibitors. more...
- Published
- 2023
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33. mRNA splicing is modulated by intronic microRNAs
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Luba Farberov, Daphna Weissglas-Volkov, Guy Shapira, Yazeed Zoabi, Chen Schiff, Barbara Kloeckener-Gruissem, John Neidhardt, and Noam Shomron
- Subjects
Molecular biology ,Cell biology ,Functional aspects of cell biology ,Science - Abstract
Summary: Splicing of transcripts is catalyzed by the spliceosome, a mega-complex consisting of hundreds of proteins and five snRNAs, which employs direct interactions. When U1 snRNA forms high-affinity binding, namely more than eight base pairs, with the 5′SS, the result is usually a suppressing effect on the splicing activity. This likely occurs due to the inefficient unwinding of U1/5′SS base-pairing or other regulatory obstructions. Here, we show in vitro and in patient-derived cell lines that pre-microRNAs can modulate the splicing reaction by interacting with U1 snRNA. This leads to reduced binding affinity to the 5′SS, and hence promotes the inclusion of exons containing 5′SS, despite sequence-based high affinity to U1. Application of the mechanism resulted in correction of the splicing defect in the disease-causing VCAN gene from an individual with Wagner syndrome. This pre-miRNA/U1 interaction can regulate the expression of alternatively spliced exons, thus extending the scope of mechanisms regulating splicing. more...
- Published
- 2023
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34. Solute Carrier Family 37 Member 2 (SLC37A2) Negatively Regulates Murine Macrophage Inflammation by Controlling Glycolysis.
- Author
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Wang, Zhan, Zhao, Qingxia, Nie, Yan, Yu, Yi, Misra, Biswapriya B, Zabalawi, Manal, Chou, Jeff W, Key, Chia-Chi C, Molina, Anthony J, Quinn, Matthew A, Fessler, Michael B, Parks, John S, McCall, Charles E, and Zhu, Xuewei more...
- Subjects
Cell Biology ,Functional Aspects of Cell Biology ,Immunology ,Metabolism ,2.1 Biological and endogenous factors - Abstract
Increased flux of glucose through glycolysis is a hallmark of inflammatory macrophages and is essential for optimal effector functions. Solute carrier (SLC) 37A2 is an endoplasmic reticulum-anchored phosphate-linked glucose-6-phosphate transporter that is highly expressed in macrophages and neutrophils. We demonstrate that SLC37A2 plays a pivotal role in murine macrophage inflammatory activation and cellular metabolic rewiring. Toll-like receptor (TLR) 4 stimulation by lipopolysaccharide (LPS) rapidly increases macrophage SLC37A2 protein expression. SLC37A2 deletion reprograms macrophages to a hyper-glycolytic process and accelerates LPS-induced inflammatory cytokine production, which partially depends on nicotinamide adenine dinucleotide (NAD+) biosynthesis. Blockade of glycolysis normalizes the differential expression of pro-inflammatory cytokines between control and SLC37A2 deficient macrophages. Conversely, overexpression of SLC37A2 lowers macrophage glycolysis and significantly reduces LPS-induced pro-inflammatory cytokine expression. In conclusion, our study suggests that SLC37A2 dampens murine macrophage inflammation by down-regulating glycolytic reprogramming as a part of macrophage negative feedback system to curtail acute innate activation. more...
- Published
- 2020
35. ER Stress Regulates Immunosuppressive Function of Myeloid Derived Suppressor Cells in Leprosy that Can Be Overcome in the Presence of IFN-γ.
- Author
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Kelly-Scumpia, Kindra M, Choi, Aaron, Shirazi, Roksana, Bersabe, Hannah, Park, Esther, Scumpia, Philip O, Ochoa, Maria T, Yu, Jing, Ma, Feiyang, Pellegrini, Matteo, and Modlin, Robert L
- Subjects
Biological Sciences ,Cell Biology ,Functional Aspects of Cell Biology ,Immune Response ,Immunology - Abstract
Myeloid derived suppressor cells (MDSCs) are a population of immature myeloid cells that suppress adaptive immune function, yet the factors that regulate their suppressive function in patients with infection remain unclear. We studied MDSCs in patients with leprosy, a disease caused by Mycobacterium leprae, where clinical manifestations present on a spectrum that correlate with immunity to the pathogen. We found that HLA-DR-CD33+CD15+ MDSCs were increased in blood from patients with disseminated/progressive lepromatous leprosy and possessed T cell-suppressive activity as compared with self-limiting tuberculoid leprosy. Mechanistically, we found ER stress played a critical role in regulating the T cell suppressive activity in these MDSCs. Furthermore, ER stress augmented IL-10 production, contributing to MDSC activity, whereas IFN-γ allowed T cells to overcome MDSC suppressive activity. These studies highlight a regulatory mechanism that links ER stress to IL-10 in mediating MDSC suppressive function in human infectious disease. more...
- Published
- 2020
36. Tyrosine-Based Signals Regulate the Assembly of Daple⋅PARD3 Complex at Cell-Cell Junctions.
- Author
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Ear, Jason, Saklecha, Anokhi, Rajapakse, Navin, Choi, Julie, Ghassemian, Majid, Kufareva, Irina, and Ghosh, Pradipta
- Subjects
Biological Sciences ,Cell Biology ,Functional Aspects of Cell Biology - Abstract
Polarized distribution of organelles and molecules inside a cell is vital for a range of cellular processes and its loss is frequently encountered in disease. Polarization during planar cell migration is a special condition in which cellular orientation is triggered by cell-cell contact. We demonstrate that the protein Daple (CCDC88C) is a component of cell junctions in epithelial cells which serves like a cellular "compass" for establishing and maintaining contact-triggered planar polarity. Furthermore, these processes may be mediated through interaction with the polarity regulator PARD3. This interaction, mediated by Daple's PDZ-binding motif (PBM) and the third PDZ domain of PARD3, is fine-tuned by tyrosine phosphorylation on Daple's PBM by receptor and non-receptor tyrosine kinases, such as Src. Hypophosphorylation strengthens the interaction, whereas hyperphosphorylation disrupts it, thereby revealing an unexpected role of Daple as a platform for signal integration and gradient sensing for tyrosine-based signals within the planar cell polarity pathway. more...
- Published
- 2020
37. Early protection against bone stress injuries by mobilization of endogenous targeted bone remodeling
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Yuanjun Ding, Yongqing Yang, Fei Xu, Zhifen Tan, Xiyu Liu, Xi Shao, Fei Kang, Zedong Yan, Erping Luo, Jing Wang, Zhuojing Luo, Jing Cai, and Da Jing
- Subjects
Orthopedics ,Vibration ,Electromagnetic waves ,Functional aspects of cell biology ,Model organism ,Science - Abstract
Summary: Bone stress injuries are common overuse injuries, especially in soldiers, athletes, and performers. In contrast to various post-injury treatments, early protection against bone stress injuries can provide greater benefit. This study explored the early protection strategies against bone stress injuries by mobilization of endogenous targeted bone remodeling. The effects of various pharmaceutical/biophysical approaches, individual or combinational, were investigated by giving intervention before fatigue loading. We optimized the dosage and administration parameters and found that early intervention with pulsed electromagnetic field and parathyroid hormone (i.e., PEMF+PTH) resulted in the most pronounced protective effects among all the approaches against the bone stress injuries. In addition, the mechanisms by which the strategy mobilizes targeted bone remodeling and enhances the self-repair capacity of bone were systematically investigated. This study proposes strategies to reduce the incidence of bone stress injuries in high-risk populations (e.g., soldiers and athletes), particularly for those before sudden increased physical training. more...
- Published
- 2023
- Full Text
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38. Dynamics of nuclear export of pre-ribosomal subunits revealed by high-speed single-molecule microscopy in live cells
- Author
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Samuel L. Junod, Mark Tingey, Joseph M. Kelich, Alexander Goryaynov, Karl Herbine, and Weidong Yang
- Subjects
Biological sciences ,Cell biology ,Functional aspects of cell biology ,Natural sciences ,Organizational aspects of cell biology ,Science - Abstract
Summary: We present a study on the nuclear export efficiency and time of pre-ribosomal subunits in live mammalian cells, using high-speed single-molecule tracking and single-molecule fluorescence resonance energy transfer techniques. Our findings reveal that pre-ribosomal particles exhibit significantly higher nuclear export efficiency compared to other large cargos like mRNAs, with around two-thirds of interactions between the pre-60S or pre-40S and the nuclear pore complexes (NPCs) resulting in successful export to the cytoplasm. We also demonstrate that nuclear transport receptor (NTR) chromosomal maintenance 1 (CRM1) plays a crucial role in nuclear export efficiency, with pre-60S and pre-40S particle export efficiency decreasing by 11–17-fold when CRM1 is inhibited. Our results suggest that multiple copies of CRM1 work cooperatively to chaperone pre-ribosomal subunits through the NPC, thus increasing export efficiency and decreasing export time. Significantly, this cooperative NTR mechanism extends beyond pre-ribosomal subunits, as evidenced by the enhanced nucleocytoplasmic transport of proteins. more...
- Published
- 2023
- Full Text
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39. Homo-oxidized HSPB1 protects H9c2 cells against oxidative stress via activation of KEAP1/NRF2 signaling pathway
- Author
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Nian Wang, Xiehong Liu, Ke Liu, Kangkai Wang, and Huali Zhang
- Subjects
Molecular biology ,Cell biology ,Functional aspects of cell biology ,Science - Abstract
Summary: Several heat shock proteins are implicated in the endogenous cardioprotective mechanisms, but little is known about the role of heat shock protein beta-1 (HSPB1). This study aims to investigate the oxidation state and role of HSPB1 in cardiomyocytes undergoing oxidative stress and underlying mechanisms. Here, we demonstrate that hydrogen peroxide (H2O2) promotes the homo-oxidation of HSPB1. Cys137 residue of HSPB1 is not only required for it to protect cardiomyocytes against oxidative injury but also modulates its oxidation, phosphorylation at Ser15, and distribution to insoluble cell components after H2O2 treatment. Moreover, Cys137 residue is indispensable for HSPB1 to interact with KEAP1, thus regulating its oxidation and intracellular distribution, subsequently promoting the nuclear translocation of NRF2, and increasing the transcription of GLCM, HMOX1, and TXNRD1. Altogether, these findings provide evidence that Cys137 residue is indispensable for HSPB1 to maintain its redox state and antioxidant activity via activating KEAP1/NRF2 signaling cascade in cardiomyocytes. more...
- Published
- 2023
- Full Text
- View/download PDF
40. TSC22D3 as an immune-related prognostic biomarker for acute myeloid leukemia
- Author
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Yang Li, Hanying Huang, Ziang Zhu, Shuzhao Chen, Yang Liang, and Lingling Shu
- Subjects
Components of the immune system ,Functional aspects of cell biology ,Cancer systems biology ,Science - Abstract
Summary: Acute myeloid leukemia (AML) is the type of hematologic neoplasm most common in adults. Glucocorticoid-induced gene TSC22D3 regulates cell proliferation through its function as a transcription factor. However, there is no consensus on the prognostic and immunoregulatory significance of TSC22D3 in AML. In the present study, we evaluated the correlation between TSC22D3 expression, immunoinfiltration, and prognostic significance in AML. Knockdown of TSC22D3 significantly attenuated the proliferation of Hel cells and increased sensitivity to cytarabine (Ara-c) drugs. Furthermore, TSC22D3 reduced the release of interleukin-1β (IL-1β) by inhibiting the NF-κB/NLRP3 signaling pathway, thereby inhibiting macrophage polarization to M1 subtype, and attenuating the pro-inflammatory tumor microenvironment. In conclusion, this study identified TSC22D3 as an immune-related prognostic biomarker for AML patients and suggested that therapeutic targeting of TSC22D3 may be a potential treatment option for AML through tumor immune escape. more...
- Published
- 2023
- Full Text
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41. The nuclear transport factor CSE1 drives macronuclear volume increase and macronuclear node coalescence in Stentor coeruleus
- Author
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Rebecca M. McGillivary, Pranidhi Sood, Katherine Hammar, and Wallace F. Marshall
- Subjects
Cell biology ,Functional aspects of cell biology ,Biophysics ,Science - Abstract
Summary: Stentor coeruleus provides a unique opportunity to study how cells regulate nuclear shape because its macronucleus undergoes a rapid, dramatic, and developmentally regulated shape change. We found that the volume of the macronucleus increases during coalescence, suggesting an inflation-based mechanism. When the nuclear transport factor, CSE1, is knocked down by RNAi, the shape and volume changes of the macronucleus are attenuated, and nuclear morphology is altered. CSE1 protein undergoes a dynamic relocalization correlated with nuclear shape changes, being mainly cytoplasmic prior to nuclear coalescence, and accumulating inside the macronucleus during coalescence. At the end of regeneration, CSE1 protein levels are reduced as the macronucleus returns to its pre-coalescence volume. We propose a model in which nuclear transport via CSE1 is required to increase the volume of the macronucleus, thereby decreasing the surface-to-volume ratio and driving coalescence of the nodes into a single mass. more...
- Published
- 2023
- Full Text
- View/download PDF
42. Changes in the hydrophobic network of the FliGMC domain induce rotational switching of the flagellar motor
- Author
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Tatsuro Nishikino, Atsushi Hijikata, Seiji Kojima, Tsuyoshi Shirai, Masatsune Kainosho, Michio Homma, and Yohei Miyanoiri
- Subjects
Cell biology ,Specialized functions of cells ,Functional aspects of cell biology ,Science - Abstract
Summary: The FliG protein plays a pivotal role in switching the rotational direction of the flagellar motor between clockwise and counterclockwise. Although we previously showed that mutations in the Gly-Gly linker of FliG induce a defect in switching rotational direction, the detailed molecular mechanism was not elucidated. Here, we studied the structural changes in the FliG fragment containing the middle and C-terminal regions, named FliGMC, and the switch-defective FliGMC-G215A, using nuclear magnetic resonance (NMR) and molecular dynamics simulations. NMR analysis revealed multiple conformations of FliGMC, and the exchange process between these conformations was suppressed by the G215A residue substitution. Furthermore, changes in the intradomain orientation of FliG were induced by changes in hydrophobic interaction networks throughout FliG. Our finding applies to FliG in a ring complex in the flagellar basal body, and clarifies the switching mechanism of the flagellar motor. more...
- Published
- 2023
- Full Text
- View/download PDF
43. Restoration of mitochondrial function by Spirulina polysaccharide via upregulated SOD2 in aging fibroblasts
- Author
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Kayo Machihara, Shoma Oki, Yuka Maejima, Sou Kageyama, Ayumu Onda, Yurino Koseki, Yasuyuki Imai, and Takushi Namba
- Subjects
Cell biology ,Cellular physiology ,Functional aspects of cell biology ,Science - Abstract
Summary: Reactive oxygen species (ROS), such as superoxide, are crucial factors involved in the stimulation of cellular aging. Mitochondria, which are important organelles responsible for various metabolic processes in cells, produce ROS. These ROS impair mitochondrial function, thereby accelerating aging-related cellular dysfunction. Herein, we demonstrated that the Spirulina polysaccharide complex (SPC) restores mitochondrial function and collagen production by scavenging superoxide via the upregulation of superoxide dismutase 2 (SOD2) in aging fibroblasts. We observed that SOD2 expression was linked to inflammatory pathways; however, SPC did not upregulate the expression of most inflammatory cytokines produced as a result of induction of LPS in aging fibroblasts, indicating that SPC induces SOD2 without activation of inflammatory pathways. Furthermore, SPC stimulated endoplasmic reticulum (ER) protein folding by upregulating ER chaperones expression. Thus, SPC is proposed to be an antiaging material that rejuvenates aging fibroblasts by increasing their antioxidant potential via the upregulation of SOD2. more...
- Published
- 2023
- Full Text
- View/download PDF
44. Genome-wide CRISPR-Cas9 screen analyzed by SLIDER identifies network of repressor complexes that regulate TRIM24
- Author
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Lalit R. Patel, Sabrina A. Stratton, Megan McLaughlin, Patrick Krause, Kendra Allton, Andrés López Rivas, Daniela Barbosa, Traver Hart, and Michelle C. Barton
- Subjects
Cell biology ,Functional aspects of cell biology ,Biocomputational method ,Biochemical classification methods ,Science - Abstract
Summary: TRIM24 is an oncogenic chromatin reader that is frequently overexpressed in human tumors and associated with poor prognosis. However, TRIM24 is rarely mutated, duplicated, or rearranged in cancer. This raises questions about how TRIM24 is regulated and what changes in its regulation are responsible for its overexpression. Here, we perform a genome-wide CRISPR-Cas9 screen by fluorescence-activated cell sorting (FACS) that nominated 220 negative regulators and elucidated a regulatory network that includes the KAP1 corepressor, CNOT deadenylase, and GID/CTLH E3 ligase. Knocking out required components of these three complexes caused TRIM24 overexpression, confirming their negative regulation of TRIM24. Our findings identify regulators of TRIM24 that nominate previously unexplored contexts for this oncoprotein in biology and disease. These findings were enabled by SLIDER, a new scoring system designed and vetted in our study as a broadly applicable tool for analysis of CRISPR screens performed by FACS. more...
- Published
- 2023
- Full Text
- View/download PDF
45. Enhanced TGF-β Signaling Contributes to the Insulin-Induced Angiogenic Responses of Endothelial Cells.
- Author
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Budi, Erine H, Mamai, Ons, Hoffman, Steven, Akhurst, Rosemary J, and Derynck, Rik
- Subjects
Cell Biology ,Functional Aspects of Cell Biology ,Molecular Biology ,Molecular Mechanism of Behavior - Abstract
Angiogenesis, the development of new blood vessels, is a key process in disease. We reported that insulin promotes translocation of transforming growth factor β (TGF-β) receptors to the plasma membrane of epithelial and fibroblast cells, thus enhancing TGF-β responsiveness. Since insulin promotes angiogenesis, we addressed whether increased autocrine TGF-β signaling participates in endothelial cell responses to insulin. We show that insulin enhances TGF-β responsiveness and autocrine TGF-β signaling in primary human endothelial cells, by inducing a rapid increase in cell surface TGF-β receptor levels. Autocrine TGF-β/Smad signaling contributed substantially to insulin-induced gene expression associated with angiogenesis, including TGF-β target genes encoding angiogenic mediators; was essential for endothelial cell migration; and participated in endothelial cell invasion and network formation. Blocking TGF-β signaling impaired insulin-induced microvessel outgrowth from neonatal aortic rings and modified insulin-stimulated blood vessel formation in zebrafish. We conclude that enhanced autocrine TGF-β signaling is integral to endothelial cell and angiogenic responses to insulin. more...
- Published
- 2019
46. How chromosomal translocations arise to cause cancer: Gene proximity, trans-splicing, and DNA end joining
- Author
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Patrick Streb, Eric Kowarz, Tamara Benz, Jennifer Reis, and Rolf Marschalek
- Subjects
Molecular biology ,Cell biology ,Functional aspects of cell biology ,Science - Abstract
Summary: Chromosomal translocations (CTs) are a genetic hallmark of cancer. They could be identified as recurrent genetic aberrations in hemato-malignancies and solid tumors. More than 40% of all “cancer genes” were identified in recurrent CTs. Most of these CTs result in the production of oncofusion proteins of which many have been studied over the past decades. They influence signaling pathways and/or alter gene expression. However, a precise mechanism for how these CTs arise and occur in a nearly identical fashion in individuals remains to be elucidated. Here, we performed experiments that explain the onset of CTs: (1) proximity of genes able to produce prematurely terminated transcripts, which lead to the production of (2) trans-spliced fusion RNAs, and finally, the induction of (3) DNA double-strand breaks which are subsequently repaired via EJ repair pathways. Under these conditions, balanced chromosomal translocations could be specifically induced. The implications of these findings will be discussed. more...
- Published
- 2023
- Full Text
- View/download PDF
47. Effect of mitophagy in the formation of osteomorphs derived from osteoclasts
- Author
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Tingben Huang, Yuchen Wang, Zhou Yu, Xiaoyan Miao, Zhiwei Jiang, Ke Yu, Mengdie Fu, Kaichen Lai, Ying Wang, and Guoli Yang
- Subjects
Molecular interaction ,Specialized functions of cells ,Functional aspects of cell biology ,Science - Abstract
Summary: Osteoclasts are specialized multinucleated giant cells with unique bone-destroying capacities. A recent study revealed that osteoclasts undergo an alternative cell fate by dividing into daughter cells called osteomorphs. To date, no studies have focused on the mechanisms of osteoclast fission. In this study, we analyzed the alternative cell fate process in vitro and, herein, reported the high expression of mitophagy-related proteins during osteoclast fission. Mitophagy was further confirmed by the colocalization of mitochondria with lysosomes, as observed in fluorescence images and transmission electron microscopy. We investigated the role played by mitophagy in osteoclast fission via drug stimulation experiments. The results showed that mitophagy promoted osteoclast division, and inhibition of mitophagy induced osteoclast apoptosis. In summary, this study reveals the role played by mitophagy as the decisive link in osteoclasts’ fate, providing a new therapeutic target and perspective for the clinical treatment of osteoclast-related diseases. more...
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- 2023
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48. Creatine kinase brain-type regulates BCAR1 phosphorylation to facilitate DNA damage repair
- Author
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Bo Yang, Wentao Zhang, Le Sun, Bin Lu, Changsong Yin, Yaoyang Zhang, and Hong Jiang
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Biochemistry ,Molecular biology ,Molecular mechanism of gene regulation ,Cell biology ,Functional aspects of cell biology ,Proteomics ,Science - Abstract
Summary: Creatine kinase (CK) is an essential metabolic enzyme mediating creatine/phosphocreatine interconversion and shuttle to replenish ATP for energy needs. Ablation of CK causes a deficiency in energy supply that eventually results in reduced muscle burst activity and neurological disorders in mice. Besides the well-established role of CK in energy-buffering, the mechanism underlying the non-metabolic function of CK is poorly understood. Here we demonstrate that creatine kinase brain-type (CKB) may function as a protein kinase to regulate BCAR1 Y327 phosphorylation that enhances the association between BCAR1 and RBBP4. Then the complex of BCAR1 and RPPB4 binds to the promoter region of DNA damage repair gene RAD51 and activates its transcription by modulating histone H4K16 acetylation to ultimately promote DNA damage repair. These findings reveal the possible role of CKB independently of its metabolic function and depict the potential pathway of CKB-BCAR1-RBBP4 operating in DNA damage repair. more...
- Published
- 2023
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49. Latent CSN-CRL complexes are crucial for curcumin-induced apoptosis and recruited during adipogenesis to lipid droplets via small GTPase RAB18
- Author
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Dawadschargal Dubiel, Jing Wang, Roland Hartig, Supattra Chaithongyot, Wolfgang Dubiel, and Michael Naumann
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Cellular physiology ,Cell biology ,Functional aspects of cell biology ,Science - Abstract
Summary: The COP9 signalosome (CSN) and cullin-RING ubiquitin ligases (CRLs) form latent CSN-CRL complexes detectable in cells. We demonstrate that the CSN variants CSNCSN7A and CSNCSN7B preferentially bind to CRL3 or CRL4A and CRL4B, respectively. Interestingly, the interacting protein ubiquitin-specific protease 15 exclusively binds to latent CSNCSN7A-CRL3, while p27KIP attaches to latent CSNCSN7B-CRL4A complex. Inhibition of deneddylation by CSN5i-3 or neddylation by MLN4924 do not impede the formation of latent complexes. Latent CSNCSN7A-CRL3 and latent CSNCSN7B-CRL4A/B particles are essential for specific cellular functions. We found that curcumin-induced cell death requires latent CSNCSN7B-CRL4A. Knockout of CSN7B in HeLa cells leads to resistance against curcumin. Remarkably, the small GTPase RAB18 recruits latent CSNCSN7A-CRL3 complex to lipid droplets (LDs), where CRL3 is activated by neddylation, an essential event for LD formation during adipogenesis. Knockdown of CSN7A or RAB18 or destabilization of latent complexes by cutting off CSN7A C-terminal 201–275 amino acids blocks adipogenesis. more...
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- 2023
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50. A rationally designed optochemogenetic switch for activating canonical Wnt signaling
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Seunghwan Lee, Mingguang Cui, Donghun Lee, Kihoon Han, Woong Sun, and Dongmin Lee
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Biochemistry methods ,Functional aspects of cell biology ,Methodology in biological sciences ,Science - Abstract
Summary: Accurate spatiotemporal control of multicellular self-organization by various signaling pathways is essential for developmental stages. In particular, evolutionarily conserved Wnt signaling serves as a major morphogenetic switch to determine the anteroposterior axis of the embryo. Here, we developed a genetically encoded optochemogenetic Wnt switch, named optochemoWnt, by coupling a blue light-inducible CRY2olig and rapamycin-inducible LRP6c clustering. The rationally designed optochemoWnt successfully modulated Wnt signaling with AND-gated patterns and demonstrated an improved signal-to-noise ratio (SNR). The dual-triggered switch provides a safeguard to prevent signal leakage resulting from ambient light sources under general laboratory conditions. OptochemoWnt expands the molecular toolbox available for the fields of developmental biology and tissue engineering. In addition, the AND-gated strategy of optochemoWnt may be used for other biomedical applications that integrate user defined switch elements with Boolean logic gates. more...
- Published
- 2023
- Full Text
- View/download PDF
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