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Brassinosteroid-insensitive 1 (BRI1)-EMS suppressor 1 (BES1) and Brassinazole-resistant 1 (BZR1) are two highly similar master transcription factors of the brassinosteroid (BR) signaling pathway that regulates a variety of plant growth and development processes as well as stress responses. Previous genetic and biochemical analyses have established a complex regulatory network to control the two transcription factors. This network includes coordination with other transcription factors and interactors, multiple post-translational modifications (PTMs) and differential subcellular localizations. In this review, we systematically detail the functions and regulatory mechanisms of various PTMs: phosphorylation/dephosphorylation, ubiquitination/deubiquitination, SUMOylation/deSUMOylation and oxidation/reduction, in regulating the subcellular localization, protein stability and the transcriptional activity of BES1/BZR1. We also discuss the current knowledge about the BES1/BZR1 interactors mediating the dynamic nucleocytoplasmic shuttling of BES1 and BZR1. [ABSTRACT FROM AUTHOR]

NFIB is a transcription factor of the Nuclear Factor One (NFI) family that is essential for embryonic development. Post‐translational control of NFIB or its upstream regulators have not been well characterized. Here, we show that PIN1 binds NFIB in a phosphorylation‐dependent manner, via its WW domain. PIN1 interacts with the well‐conserved N‐terminal domains of all NFIs. Moreover, PIN1 attenuates the transcriptional activity of NFIB; this attenuation requires substrate binding by PIN1 but not its isomerase activity. Paradoxically, we found stabilization of NFIB by PIN1. We propose that PIN1 represses NFIB function not by regulating its abundance but by inducing a conformational change. These results identify NFIB as a novel PIN1 target and posit a role for PIN1 in post‐translational regulation of NFIB and other NFIs. [ABSTRACT FROM AUTHOR]

Background: LncRNA PCAT6 has been shown to involve in carcinogenesis of different tumors. In this study, we investigated underline mechanism by which PCAT6 promoted breast cancer cell progression. Methods: RIP was used to identify lncRNAs associated with IMP1. Bioinformatics assays were used to predict potential miRNAs that interact with PCAT6 and mRNAs that are targeted by miR-545-3p. RNA-seq and RT-qPCR were used to analyze differential expression of lncRNAs and miRNA-targeted genes. Luciferase reporter and RNA pull-down assays were performed to identify the molecular interactions between PCAT6 and individual miRNAs. The role of PCAT6-mediated cell proliferation and invasion were tested by CCK-8 and transwell assays following loss-of-function and gain-of-function effects. Results: We identified that PCAT6 is one of the lncRNAs that associated with IMP1. PCAT6 not only binds to IMP1, but also acts as a ceRNA to interact with multiple miRNAs, including miR-545-3p. Binding of IMP1 destabilized PCAT6, while competitive interaction with miR-545-3p allowed PCAT6 to positively regulate UBFD1 expression. Silencing UBFD1 mRNA could effectively rescue PCAT6-induced cell proliferation and invasive abilities. Conclusions: Our study provided evidence that PCAT6 activates UBFD1 expression via sponging miR-545-3p to increase carcinogenesis of breast cancer cells. Based on the nature of UBFD1 as a polyubiquitin binding protein, our study suggested that ubiquitin pathway might contribute to breast cancer progression.

Summary: Gibberellic acid (GA) plays a central role in many plant developmental processes and is crucial for crop improvement. DELLA proteins, the core suppressors in the GA signaling pathway, are degraded by GA via the 26S proteasomal pathway to release the GA response. However, little is known about the phosphorylation‐mediated regulation of DELLA proteins.In this study, we combined GA response assays with protein–protein interaction analysis to infer the connection between Arabidopsis thaliana DELLAs and the C‐TERMINAL DOMAIN PHOSPHATASE‐LIKE 3 (CPL3), a phosphatase involved in the dephosphorylation of RNA polymerase II.We show that CPL3 directly interacts with DELLA proteins and promotes DELLA protein stability by inhibiting its degradation by the 26S proteasome. Consequently, CPL3 negatively modulates multiple GA‐mediated processes of plant development, including hypocotyl elongation, flowering time, and anthocyanin accumulation.Taken together, our findings demonstrate that CPL3 serves as a novel regulator that could improve DELLA stability and thereby participate in GA signaling transduction. [ABSTRACT FROM AUTHOR]

Disruptor of telomeric silencing 1 (Dot1p) is an exquisitely conserved histone methyltransferase and is the sole enzyme responsible for H3K79 methylation in the budding yeast Saccharomyces cerevisiae. It has been shown to be highly phosphorylated in vivo; however, the upstream kinases that act on Dot1p are almost entirely unknown in yeast and all other eukaryotes. Here, we used in vitro and in vivo kinase discovery approaches to show that mitogen‐activated protein kinase HOG1 (Hog1p) is a bona fide kinase of the Dot1p methyltransferase. In vitro kinase assays showed that Hog1p phosphorylates Dot1p at multiple sites, including at several proline‐adjacent sites that are consistent with known Hog1p substrate preferences. The activity of Hog1p was specifically enhanced at these proline‐adjacent sites on Dot1p upon Hog1p activation by the osmostress‐responsive MAP kinase kinase PBS2 (Pbs2p). Genomic deletion of HOG1 reduced phosphorylation at specific sites on Dot1p in vivo, providing further evidence for Hog1p kinase activity on Dot1p in budding yeast cells. Phenotypic analysis of knockout and phosphosite mutant yeast strains revealed the importance of Hog1p‐catalysed phosphorylation of Dot1p for cellular responses to ultraviolet‐induced DNA damage. In mammalian systems, this kinase–substrate relationship was found to be conserved: human DOT1L (the ortholog of yeast Dot1p) can be phosphorylated by the proline‐directed kinase p38β (also known as MAPK11; the ortholog of yeast Hog1p) at multiple sites in vitro. Taken together, our findings establish Hog1p and p38β as newly identified upstream kinases of the Dot1p/DOT1L H3K79 methyltransferase enzymes in eukaryotes. [ABSTRACT FROM AUTHOR]

Ascorbate peroxidase (APX) reduces H2O2 to H2O by utilizing ascorbate as a specific electron donor and constitutes the ascorbate–glutathione cycle in organelles of plants including chloroplasts, cytosol, mitochondria, and peroxisomes. It has been almost 40 years since APX was discovered as an important plant-specific H2O2-scavenging enzyme, during which time many research groups have conducted molecular physiological analyses. It is now clear that APX isoforms function not only just as antioxidant enzymes but also as important factors in intracellular redox regulation through the metabolism of reactive oxygen species. The function of APX isoforms is regulated at multiple steps, from the transcriptional level to post-translational modifications of enzymes, thereby allowing them to respond flexibly to ever-changing environmental factors and physiological phenomena such as cell growth and signal transduction. In this review, we summarize the physiological functions and regulation mechanisms of expression of each APX isoform. [ABSTRACT FROM AUTHOR]

Wheat (Triticum aestivum L.) is one of the world's most important staple crops, whose production is critical to feed the expanding population worldwide. The 90-kDa Heat Shock Protein 90 (HSP90) is a highly abundant chaperone protein involved in multiple cellular processes. It facilitates the folding of nascent preproteins for their maturation and functioning. This data described HSP90.2 clients identified from the whole genome of wheat. The HSP90.2 chaperome contains over 1500 proteins, most detected by the C terminus and full-length of HSP90.2. Over 60 % of the clients reside in the cytosol, nucleus, and chloroplasts. Cytoskeleton-related proteins are enriched in the chaperome of the N terminus of HSP90.2. The clients of the middle part of HSP90.2 contains several factors involved in ethylene biosynthesis and extracellular vesicle or organelle-related activities. Some clients related to plant hypersensitive response are induced by stripe rust. The presented dataset could isolate proteins regulated by HSP90.2 at the post-translational level.

NRT2.1, the major high affinity nitrate transporter in roots, can be phosphorylated at five different sites within the N- and the C-terminus. Here, we characterized the functional relationship of two N-terminal phosphorylation sites, S21 and S28, in Arabidopsis. Based on a site-specific correlation network, we identified a receptor kinase (HPCAL1, AT5G49770), phosphorylating NRT2.1 at S21 and resulting in active nitrate uptake. HPCAL1 itself was regulated by phosphorylation at S839 and S870 within its kinase domain. In the active state, when S839 was dephosphorylated and S870 was phosphorylated, HPCAL1 was found to interact with the N-terminus of NRT2.1, mainly when S28 was dephosphorylated. Phosphorylation of NRT2.1 at S21 resulted in a reduced interaction of NRT2.1 with its activator NAR2.1, but nitrate transport activity remained. By contrast, phosphorylated NRT2.1 at S28 enhanced the interaction with NAR2.1, but reduced the interaction with HPCAL1. Here we identified HPCAL1 as the kinase affecting this phospho-switch through phosphorylation of NRT2.1 at S21. [ABSTRACT FROM AUTHOR]

Background: Human gliomas are aggressive brain tumors characterized by uncontrolled cell proliferation. Differential expression of Polycomb repressive complex 2 (PRC2) has been reported in various subtypes of glioma. However, the role of PRC2 in uncontrolled growth in glioma and its underlying molecular mechanisms remain to be elucidated. Objective: We aimed to investigate the functional role of PRC2 in human glioblastoma cell growth by silencing SUZ12, the non-catalytic core component of PRC2. Methods: Knockdown of SUZ12 was achieved by infecting T98G cells with lentivirus carrying sequences specifically targeting SUZ12 (shSUZ12). Gene expression was examined by quantitative PCR and western analysis. The impact of shSUZ12 on cell growth was assessed using a cell proliferation assay. Cell cycle distribution was analyzed by flow cytometry, and protein stability was evaluated in cycloheximide-treated cells. Subcellular localization was examined through immunofluorescence staining and biochemical cytoplasmic-nuclear fractionation. Gene expression analysis was also performed on human specimens from normal brain and glioblastoma patients. Results: SUZ12 knockdown (SUZ12 KD) led to widespread decrease in the PRC2-specific histone mark, accompanied by a slowdown of cell proliferation through G1 arrest. In SUZ12 KD cells, the degradation of CDKN1B protein was reduced, resulting from alterations in the MYC-SKP2-CDKN1B axis. Furthermore, nuclear localization of CDKN1B was enhanced in SUZ12 KD cells. Analysis of human glioblastoma samples yielded increased expression of EZH2 and MYC along with reduced CDKN1B compared to normal human brain tissue. Conclusion: Our findings suggest a novel role for SUZ12 in cell proliferation through post-translational regulation of CDKN1B in glioblastoma. [ABSTRACT FROM AUTHOR]

TAZ (WWTR1) is a transcriptional co-activator regulated by Hippo signaling, mechano-transduction, and G-protein couple receptors. Once activated, TAZ and its paralogue, YAP1, regulate gene expression programs promoting cell proliferation, survival, and differentiation, thus controlling embryonic development, tissue regeneration, and aging. YAP and TAZ are also frequently activated in tumors, particularly in poorly differentiated and highly aggressive malignancies. Yet, mutations of YAP/TAZ or of their upstream regulators do not fully account for their activation in cancer, raising the possibility that other upstream regulatory pathways, still to be defined, are altered in tumors. In this work, we set out to identify novel regulators of TAZ by means of a siRNA-based screen. We identified 200 genes able to modulate the transcriptional activity of TAZ, with prominence for genes implicated in cell–cell contact, cytoskeletal tension, cell migration, WNT signaling, chromatin remodeling, and interleukins and NF–kappaB signaling. Among these genes we identified was BRCC3, a component of the BRCA1 complex that guards genome integrity and exerts tumor suppressive activity during cancer development. The loss of BRCC3 or BRCA1 leads to an increased level and activity of TAZ. Follow-up studies indicated that the cytoplasmic BRCA1 complex controls the ubiquitination and stability of TAZ. This may suggest that, in tumors, inactivating mutations of BRCA1 may unleash cell transformation by activating the TAZ oncogene. [ABSTRACT FROM AUTHOR]

Keywords: Biotic and abiotic stress; CRISPR/Cas9; plant nutrition; post-translational regulation; prime editing; transcriptional regulation EN Biotic and abiotic stress CRISPR/Cas9 plant nutrition post-translational regulation prime editing transcriptional regulation 5949 5954 6 10/17/23 20231013 NES 231013 B Plant molecular biology has evolved with substantial progress in recent years, in order to decipher the molecular principles that underlie plant biology. Google Scholar Crossref Search ADS Google Preview WorldCat COPAC 31 Panth M, Hassler SC, Baysal-Gurel F. 2020. Google Scholar Crossref Search ADS WorldCat 17 García I, Arenas-Alfonseca L, Moreno I, Gotor C, Romero LC. 2019. The biannual Plant Molecular Biology Meeting, which was the impetus for this Special Issue, is a great example of a scientific meeting where molecular plant biologists discuss new techniques and strategies to improve crop production. [Extracted from the article]

Deterioration and impoverishment of soil, caused by environmental pollution and climate change, result in reduced crop productivity. To adapt to hostile soils, plants have developed a complex network of factors involved in stress sensing, signal transduction, and adaptive responses. The chemical properties of reactive oxygen species (ROS) and reactive nitrogen species (RNS) allow them to participate in integrating the perception of external signals by fine-tuning protein redox regulation and signal transduction, triggering specific gene expression. Here, we update and summarize progress in understanding the mechanistic basis of ROS and RNS production at the subcellular level in plants and their role in the regulation of ion channels/transporters at both transcriptional and post-translational levels. We have also carried out an in silico analysis of different redox-dependent modifications of ion channels/transporters and identified cysteine and tyrosine targets of nitric oxide in metal transporters. Further, we summarize possible ROS- and RNS-dependent sensors involved in metal stress sensing, such as kinases and phosphatases, as well as some ROS/RNS-regulated transcription factors that could be involved in metal homeostasis. Understanding ROS- and RNS-dependent signaling events is crucial to designing new strategies to fortify crops and improve plant tolerance of nutritional imbalance and metal toxicity. [ABSTRACT FROM AUTHOR]

Abstract Background In vivo investigations with cancer cells have powerful tools to discover cancer progression mechanisms and preclinical candidate drugs. Among these in vivo experimental models, the establishment of highly malignancy cell lines with xenograft has been frequently used. However, few previous researches targeted malignancy-related genes whose protein levels translationally changed. Therefore, this study aimed to identify malignancy-related genes which contributed to cancer progression and changed at the protein level in the in vivo selected cancer cell lines. Methods We established the high malignancy breast cancer cell line (LM05) by orthotopic xenograft as an in vivo selection method. To explore the altered genes by translational or post-translational regulation, we analyzed the protein production by western blotting in the highly malignant breast cancer cell line. Functional analyses of the altered genes were performed by in vitro and in vivo experiments. To reveal the molecular mechanisms of the regulation with protein level, we evaluated post-translational modification by immunoprecipitation. In addition, we evaluated translational production by click reaction-based purification of nascent protein. Results As a result, NF-κB inducing kinase (NIK) increased at the protein level and promoted the nuclear localization of NF-κB2 (p52) and RelB in the highly malignant breast cancer cell line. The functional analyses indicated the NIK upregulation contributed to tumor malignancy via cancer-associated fibroblasts (CAFs) attraction and partially anti-apoptotic activities. Additionally, the immunoprecipitation experiment revealed that the ubiquitination of NIK decreased in LM05 cells. The decline in NIK ubiquitination was attributed to the translational downregulation of cIAP1. Conclusions Our study identified a dysregulated mechanism of NIK production by the suppression of NIK post-modification and cIAP1 translation. The aberrant NIK accumulation promoted tumor growth in the highly malignant breast cancer cell line.

Background: Neurodegenerative diseases are a common group of neurological disorders characterized by progressive loss of neuronal structure and function leading to cognitive impairment. Recent studies have shown that neuronal pyroptosis mediated by the NLRP3 inflammasome plays a crucial role in the pathogenesis of neurodegenerative diseases. Objective and method: The NLRP3 inflammasome is a multiprotein complex that, when activated within cells, triggers an inflammatory response, ultimately leading to pyroptotic cell death of neurons. Pyroptosis is a typical pro-inflammatory programmed cell death process occurring downstream of NLRP3 inflammasome activation, characterized by the formation of pores on the cell membrane by the GSDMD protein, leading to cell lysis and the release of inflammatory factors. It has been found that NLRP3 inflammasome-mediated neuronal pyroptosis is closely associated with the development of various neurodegenerative diseases, such as Alzheimer's disease, traumatic brain injury, and Parkinson's disease. Therefore, inhibiting NLRP3 inflammasome activation and attenuating neuronal pyroptosis could potentially serve as novel strategies for the treatment of neurodegenerative diseases. Results: The aim of this review is to explore the role of NLRP3 activation-mediated neuronal pyroptosis and neuroinflammation in neurodegenerative diseases. Firstly, we extensively discuss the relationship between NLRP3 inflammasome-mediated neuronal pyroptosis and neuroinflammation in various neurodegenerative diseases. Subsequently, we further explore the mechanisms driving NLRP3 activation and assembly, as well as the post-translational modifications regulating NLRP3 inflammasome activation. Conclusion: Understanding these mechanisms will contribute to a deeper understanding of the link between neuronal pyroptosis and neurodegenerative diseases, and hold significant implications for the treatment and prevention of neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

In the past few years, numerous advances emerged in terms of circulating microRNA(miRNA) regulating gene expression by circulating blood to the distal tissues and cells. This article reviewed and summarized the process of circulating miRNAs entering the circulating system to exert gene regulation, especially exogenous miRNAs (such as plant miRNAs), from the perspective of the circulating miRNAs source (cell secretion or gastrointestinal absorption), the transport form and pharmacokinetics in circulating blood, and the evidence of distal regulation to gene expression, thereby providing a basis for their in-depth research and even application prospects. [ABSTRACT FROM AUTHOR]

Over the past decades, extensive research has been conducted to identify and characterize various plant transcription factors involved in abiotic stress responses. Therefore, numerous efforts have been made to improve plant stress tolerance by engineering these transcription factor genes. The plant basic Helix–Loop–Helix (bHLH) transcription factor family represents one of the most prominent gene families and contains a bHLH motif that is highly conserved in eukaryotic organisms. By binding to specific positions in promoters, they activate or repress the transcription of specific response genes and thus affect multiple variables in plant physiology such as the response to abiotic stresses, which include drought, climatic variations, mineral deficiencies, excessive salinity, and water stress. The regulation of bHLH transcription factors is crucial to better control their activity. On the one hand, they are regulated at the transcriptional level by other upstream components; on the other hand, they undergo various modifications such as ubiquitination, phosphorylation, and glycosylation at the post-translational level. Modified bHLH transcription factors can form a complex regulatory network to regulate the expression of stress response genes and thus determine the activation of physiological and metabolic reactions. This review article focuses on the structural characteristics, classification, function, and regulatory mechanism of bHLH transcription factor expression at the transcriptional and post-translational levels during their responses to various abiotic stress conditions. [ABSTRACT FROM AUTHOR]

SUMMARY: Carnation (Dianthus caryophyllus L.) is a respiratory climacteric flower, comprising one of the most important cut flowers that is extremely sensitive to plant hormone ethylene. Ethylene signaling core transcription factor DcEIL3‐1 plays a key role in ethylene induced petal senescence in carnation. However, how the dose of DcEIL3‐1 is regulated in the carnation petal senescence process is still not clear. Here, we screened out two EBF (EIN3 Binding F‐box) genes, DcEBF1 and DcEBF2, which showed quick elevation by ethylene treatment according to the ethylene induced carnation petal senescence transcriptome. Silencing of DcEBF1 and DcEBF2 accelerated, whereas overexpression of DcEBF1 and DcEBF2 delayed, ethylene induced petal senescence in carnation by influencing DcEIL3‐1 downstream target genes but not DcEIL3‐1 itself. Furthermore, DcEBF1 and DcEBF2 interact with DcEIL3‐1 to degrade DcEIL3‐1 via an ubiquitination pathway in vitro and in vivo. Finally, DcEIL3‐1 binds to the promoter regions of DcEBF1 and DcEBF2 to activate their expression. In conclusion, the present study reveals the mutual regulation between DcEBF1/2 and DcEIL3‐1 during ethylene induced petal senescence in carnation, which not only expands our understanding about ethylene signal regulation network in the carnation petal senescence process, but also provides potential targets with respect to breeding a cultivar of long‐lived cut carnation. Significance Statement: Carnation is a typical ethylene sensitive cut flower worldwide and DcEIL3‐1 transcription factor plays important role in ethylene induced petal senescence in carnation. However, how ethylene regulates DcEIL3‐1 itself remains largely unknown. We found that there is a mutual regulation between DcEBF1/2 and DcEIL3‐1 at the transcriptional and post‐translational levels, which indicates that the negative feedback regulation loop plays a key role in regulating the petal senescence process. [ABSTRACT FROM AUTHOR]

This Special Issue discusses, for example, chronic pain due to nerve injury [[4]], chronic pain associated with a genetic disease [[6]], or chronic pain associated with cancer [[7]]. Since chronic pain is not a pure prolongation of acute pain, but is based on structural and functional alterations of neural circuity [[3]], understanding the molecular mechanisms underlying these alterations is crucial for developing new effective therapies. Keywords: molecular mechanisms; chronic pain; genetic; epigenetic; post-translational regulation; nociceptors; pain circuits EN molecular mechanisms chronic pain genetic epigenetic post-translational regulation nociceptors pain circuits 1126 5 05/02/23 20230415 NES 230415 Chronic pain affects a significant amount of the population and is responsible for vast worldwide socio-economic costs [[1]]. Moreover, conventional therapies are not very effective in reducing pain [[2]]; in fact, clinicians report only 50 percent pain relief among patients who respond to treatments. [Extracted from the article]

Background: In vivo investigations with cancer cells have powerful tools to discover cancer progression mechanisms and preclinical candidate drugs. Among these in vivo experimental models, the establishment of highly malignancy cell lines with xenograft has been frequently used. However, few previous researches targeted malignancy-related genes whose protein levels translationally changed. Therefore, this study aimed to identify malignancy-related genes which contributed to cancer progression and changed at the protein level in the in vivo selected cancer cell lines. Methods: We established the high malignancy breast cancer cell line (LM05) by orthotopic xenograft as an in vivo selection method. To explore the altered genes by translational or post-translational regulation, we analyzed the protein production by western blotting in the highly malignant breast cancer cell line. Functional analyses of the altered genes were performed by in vitro and in vivo experiments. To reveal the molecular mechanisms of the regulation with protein level, we evaluated post-translational modification by immunoprecipitation. In addition, we evaluated translational production by click reaction-based purification of nascent protein. Results: As a result, NF-κB inducing kinase (NIK) increased at the protein level and promoted the nuclear localization of NF-κB2 (p52) and RelB in the highly malignant breast cancer cell line. The functional analyses indicated the NIK upregulation contributed to tumor malignancy via cancer-associated fibroblasts (CAFs) attraction and partially anti-apoptotic activities. Additionally, the immunoprecipitation experiment revealed that the ubiquitination of NIK decreased in LM05 cells. The decline in NIK ubiquitination was attributed to the translational downregulation of cIAP1. Conclusions: Our study identified a dysregulated mechanism of NIK production by the suppression of NIK post-modification and cIAP1 translation. The aberrant NIK accumulation promoted tumor growth in the highly malignant breast cancer cell line. [ABSTRACT FROM AUTHOR]

Although plant metabolic engineering enables the sustainable production of valuable metabolites with many applications, we still lack a good understanding of many multi-layered regulatory networks that govern metabolic pathways at the metabolite, protein, transcriptional and cellular level. As transcriptional regulation is better understood and often reviewed, here we highlight recent advances in the cell type-specific and post-translational regulation of plant specialized metabolism. With the advent of single-cell technologies, we are now able to characterize metabolites and their transcriptional regulators at the cellular level, which can refine our searches for missing biosynthetic enzymes and cell type-specific regulators. Post-translational regulation through enzyme inhibition, protein phosphorylation and ubiquitination are clearly evident in specialized metabolism regulation, but not frequently studied or considered in metabolic engineering efforts. Finally, we contemplate how advances in cell type-specific and post-translational regulation can be applied in metabolic engineering efforts in planta , leading to optimization of plants as metabolite production vehicles. [ABSTRACT FROM AUTHOR]

TAZ (WWTR1) is a transcriptional co-activator regulated by Hippo signaling, mechano-transduction, and G-protein couple receptors. Once activated, TAZ and its paralogue, YAP1, regulate gene expression programs promoting cell proliferation, survival, and differentiation, thus controlling embryonic development, tissue regeneration, and aging. YAP and TAZ are also frequently activated in tumors, particularly in poorly differentiated and highly aggressive malignancies. Yet, mutations of YAP/TAZ or of their upstream regulators do not fully account for their activation in cancer, raising the possibility that other upstream regulatory pathways, still to be defined, are altered in tumors. In this work, we set out to identify novel regulators of TAZ by means of a siRNA-based screen. We identified 200 genes able to modulate the transcriptional activity of TAZ, with prominence for genes implicated in cell–cell contact, cytoskeletal tension, cell migration, WNT signaling, chromatin remodeling, and interleukins and NF–kappaB signaling. Among these genes we identified was BRCC3, a component of the BRCA1 complex that guards genome integrity and exerts tumor suppressive activity during cancer development. The loss of BRCC3 or BRCA1 leads to an increased level and activity of TAZ. Follow-up studies indicated that the cytoplasmic BRCA1 complex controls the ubiquitination and stability of TAZ. This may suggest that, in tumors, inactivating mutations of BRCA1 may unleash cell transformation by activating the TAZ oncogene.

Simple Summary: MicroRNAs (miRNAs) regulate messenger RNA (mRNA) expression at the post-transcriptional level. They play an important role within physiological and pathological cellular processes by regulating an estimated 60% of all protein-coding genes. miRNAs are produced quickly through canonical or non-canonical pathways involving many steps and proteins. In cancer, these steps can be altered to promote tumour formation and progression. These aberrations can occur at the gene level, or can be induced during processing and regulation of the target mRNA. This review provides an overview of the current knowledge on the lifecycle of miRNAs in health and cancer. Understanding miRNA function and regulation is essential prior to potential future application of miRNAs as cancer biomarkers. MicroRNAs (miRNAs) are small non-coding RNAs of ~22 nucleotides that regulate gene expression at the post-transcriptional level. They can bind to around 60% of all protein-coding genes with an average of 200 targets per miRNA, indicating their important function within physiological and pathological cellular processes. miRNAs can be quickly produced in high amounts through canonical and non-canonical pathways that involve a multitude of steps and proteins. In cancer, miRNA biogenesis, availability and regulation of target expression can be altered to promote tumour progression. This can be due to genetic causes, such as single nucleotide polymorphisms, epigenetic changes, differences in host gene expression, or chromosomal remodelling. Alternatively, post-transcriptional changes in miRNA stability, and defective or absent components and mediators of the miRNA-induced silencing complex can lead to altered miRNA function. This review provides an overview of the current knowledge on the lifecycle of miRNAs in health and cancer. Understanding miRNA function and regulation is fundamental prior to potential future application of miRNAs as cancer biomarkers. [ABSTRACT FROM AUTHOR]

Maintenance of the tightly regulated homeostatic environment of the brain is facilitated by the blood–brain barrier (BBB). P-glycoprotein (P-gp), an ATP-binding cassette transporter, is expressed on the luminal surface of the endothelial cells in the BBB, and actively exports a wide variety of substrates to limit exposure of the vulnerable brain environment to waste buildup and neurotoxic compounds. Downregulation of P-gp expression and activity at the BBB have been reported with ageing and in neurodegenerative diseases. Upregulation of P-gp at the BBB contributes to poor therapeutic outcomes due to altered pharmacokinetics of CNS-acting drugs. The regulation of P-gp is highly complex, but unravelling the mechanisms involved may help the development of novel and nuanced strategies to modulate P-gp expression for therapeutic benefit. This review summarises the current understanding of P-gp regulation in the brain, encompassing the transcriptional, post-transcriptional and post-translational mechanisms that have been identified to affect P-gp expression and transport activity. [ABSTRACT FROM AUTHOR]

Recent studies have revealed the complex and flexible transcriptional regulatory network involved in cold-stress responses. Focusing on two major signaling pathways that respond to cold stress, we outline current knowledge of the transcriptional regulatory network and the post-translational regulation of transcription factors in the network. Cold-stress signaling pathways are closely associated with other signaling pathways such as those related to the circadian clock, and large amounts of data on their crosstalk and tradeoffs are available. However, it remains unknown how plants sense and transmit cold-stress signals to regulate gene expression. We discuss recent reports on cold-stress sensing and associated signaling pathways that regulate the network. We also emphasize future directions for developing abiotic stress-tolerant crop plants. DREB1/CBF transcription factors function as master regulators in the transcriptional regulatory network for acquiring cold-stress tolerance, and DREB1 genes themselves are rapidly induced by cold stress. Arabidopsis thaliana uses two different signaling pathways for inducing the expression of DREB1 genes in response to cold stress. In one signaling pathway, CAMTA transcription factors containing a calmodulin-binding domain activate DREB 1 expression in response to a rapid temperature decrease. In the other signaling pathway, multiple circadian clock-related transcription factors regulate DREB1 expression during the daytime. Their post-translational regulation triggers the expression of many cold-inducible genes including DREB1. Several membrane-localized proteins associated with cytosolic Ca2+ increases, photoreceptors, and core components of the circadian clock can perceive temperature decreases. [ABSTRACT FROM AUTHOR]

Splicing is a fundamental process in pre-mRNA maturation. Whereas alternative splicing (AS) enriches the diversity of the proteome, its aberrant regulation can drive oncogenesis. So far, most attention has been given to spliceosome mutations (SMs) in the context of splicing dysregulation in hematologic diseases. However, in recent years, post-translational modifications (PTMs) and transcriptional alterations of splicing factors (SFs), just as epigenetic signatures, have all been shown to contribute to global splicing dysregulation as well. In addition, the contribution of aberrant splicing to the neoantigen repertoire of cancers has been recognized. With the pressing need for novel therapeutics to combat blood cancers, this article provides an overview of emerging mechanisms that contribute to aberrant splicing, as well as their clinical potential. Recent studies have revealed various mechanisms of splicing dysregulation in blood malignancies and their impact on crucial oncogenic pathways. As such, the implications of oncogenic splicing in hematologic malignancies, their immunologic aspects, and opportunities for therapeutic intervention require attention. Numerous forms of hematologic malignancies remain areas of unmet medical need for improved therapies. A major reason is the limited number of therapeutic options. Splicing-modulating agents may fill this need (clinical studies ongoing). Whereas spliceosome mutations are highly abundant among particular blood cancer cohorts, other mechanisms (e.g., post-translational modifications and transcriptional alterations of splicing factors, as well as epigenetic signatures of to-be-spliced genes and transcripts) have been shown to contribute to splicing dysregulation. Most of those mechanisms are therapeutically exploitable. Splicing inhibitors have been considered as putative therapeutical options for patients with spliceosome mutations. However, recent data indicate that this mechanism might not be universal and might be compensated by combination treatments in spliceosome wild-type cancers. [ABSTRACT FROM AUTHOR]

The current belief is that amino acid sequences in protein structures are defined by DNA sequences. I challenge this concept by hypothesizing that an arginine (Arg) residue in the protein structure can post-translationally be converted to a proline (Pro) residue through a redox mechanism. Reactive oxygen species promote the formation of protein carbonylation, particularly on Arg and Pro residues, which both produce glutamyl semialdehyde. Our previous studies suggested that the Pro-to-glutamyl semialdehyde reaction could be reversible in the biological system, thereby opening up a pathway for the conversion of Arg to glutamyl semialdehyde by oxidation, and subsequently, to Pro by reduction in the protein structure. Our mass spectrometry and immunoblotting experiments provided evidence of the occurrence of the Arg-to-Pro conversion at position 108 (R108P) of the peroxiredoxin 6 (Prx6) protein in biological tissues and cells. In the human brain, Prx6 (R108P) occurs, and some Alzheimer's brains exhibit increased Prx6 (R108P) levels, while others show decreased levels, indicating the complexity of redox processes in the disease state. I propose that Prx6 (R108P), as well as other post-translationally regulated protein Arg-to-Pro conversions, occur in the human body and play physiological and pathological roles. [ABSTRACT FROM AUTHOR]

Abstract Background Microbiome interactions are important determinants for ecosystem functioning, stability, and health. In previous studies, it was often observed that bacteria suppress potentially pathogenic fungal species that are part of the same plant microbiota; however, the underlying microbe-microbe interplay remains mostly elusive. Here, we explored antagonistic interactions of the fungus Fusarium graminearum and bacterium Streptomyces hygroscopicus at the molecular level. Both are ubiquitous members of the healthy wheat microbiota; under dysbiosis, the fungus causes devastating diseases. Results In co-cultures, we found that Streptomyces alters the fungal acetylome leading to substantial induction of fungal autophagy. The bacterium secrets rapamycin to inactivate the target of rapamycin (TOR), which subsequently promotes the degradation of the fungal histone acetyltransferase Gcn5 through the 26S proteasome. Gcn5 negatively regulates fungal autophagy by acetylating the autophagy-related protein Atg8 at the lysine site K13 and blocking cellular relocalization of Atg8. Thus, degradation of Gcn5 triggered by rapamycin was found to reduce Atg8 acetylation, resulting in autophagy induction in F. graminearum. Conclusions Autophagy homeostasis plays an essential role in fungal growth and competition, as well as for virulence. Our work reveals a novel post-translational regulation of autophagy initiated by a bacterial antibiotic. Rapamycin was shown to be a powerful modulator of bacteria–fungi interactions with potential importance in explaining microbial homeostasis in healthy plant microbiomes. The autophagic process provides novel possibilities and targets to biologically control pathogens. Video abstract

Over the past decades, extensive research has been conducted to identify and characterize various plant transcription factors involved in abiotic stress responses. Therefore, numerous efforts have been made to improve plant stress tolerance by engineering these transcription factor genes. The plant basic Helix–Loop–Helix (bHLH) transcription factor family represents one of the most prominent gene families and contains a bHLH motif that is highly conserved in eukaryotic organisms. By binding to specific positions in promoters, they activate or repress the transcription of specific response genes and thus affect multiple variables in plant physiology such as the response to abiotic stresses, which include drought, climatic variations, mineral deficiencies, excessive salinity, and water stress. The regulation of bHLH transcription factors is crucial to better control their activity. On the one hand, they are regulated at the transcriptional level by other upstream components; on the other hand, they undergo various modifications such as ubiquitination, phosphorylation, and glycosylation at the post-translational level. Modified bHLH transcription factors can form a complex regulatory network to regulate the expression of stress response genes and thus determine the activation of physiological and metabolic reactions. This review article focuses on the structural characteristics, classification, function, and regulatory mechanism of bHLH transcription factor expression at the transcriptional and post-translational levels during their responses to various abiotic stress conditions.

Chronic pain affects a significant amount of the population and is responsible for vast worldwide socio-economic costs [...]

Proteins usually assemble oligomers or high‐order complexes to increase their efficiency and specificity in biological processes. The dynamic equilibrium of complex formation and disruption imposes reversible regulation of protein function. MicroProteins are small, single‐domain proteins that directly bind target protein complexes and disrupt their assembly. Growing evidence shows that microProteins are efficient regulators of protein activity at the post‐translational level. In the last few decades, thousands of plant microProteins have been predicted by computational approaches, but only a few have been experimentally validated. Recent studies highlighted the mechanistic working modes of newly‐identified microProteins in Arabidopsis and other plant species. Here, we review characterized microProteins, including their biological roles, regulatory targets, and modes of action. In particular, we focus on microProtein‐directed allosteric modulation of key components in light signaling pathways, and we summarize the biogenesis and evolutionary trajectory of known microProteins in plants. Understanding the regulatory mechanisms of microProteins is an important step towards potential utilization of microProteins as versatile biotechnological tools in crop bioengineering. [ABSTRACT FROM AUTHOR]

Hepatitis B virus (HBV) is a globally prevalent human DNA virus responsible for more than 250 million cases of chronic liver infection, a condition that can lead to liver inflammation, cirrhosis, and hepatocellular carcinoma. Sodium taurocholate co-transporting polypeptide (NTCP), a transmembrane protein highly expressed in human hepatocytes and a mediator of bile acid transport, has been identified as the receptor responsible for the cellular entry of both HBV and its satellite, hepatitis delta virus (HDV). This has led to significant advances in our understanding of the HBV life cycle, especially the early steps of infection. HepG2-NTCP cells and human NTCP-expressing transgenic mice have been employed as the primary cell culture and animal models, respectively, for the study of HBV, and represent valuable approaches for investigating its basic biology and developing treatments for infection. However, the mechanisms involved in the regulation of NTCP transcription, translation, post-translational modification, and transport are still largely elusive. Improvements in our understanding of NTCP biology would likely facilitate the design of new therapeutic drugs for the prevention of the de novo infection of naïve hepatocytes. In this review, we provide critical findings regarding NTCP biology and discuss important questions that remain unanswered.

Summary: Auxin is the 'growth hormone' and modulation of its concentration correlates with changes in photosynthesis and respiration, influencing the cellular energy budget for biosynthesis and proliferation. However, the relative importance of mechanisms by which auxin directly influences photosynthesis and respiration, or vice versa, are unclear. Here we bring together recent evidence linking auxin with photosynthesis, plastid biogenesis, mitochondrial metabolism and retrograde signalling and through it we propose three hypotheses to test to unify current findings. These require delving into the control of auxin conjugation to primary metabolic intermediates, translational control under auxin regulation and post‐translational influences of auxin on primary metabolic processes. [ABSTRACT FROM AUTHOR]

The immune checkpoint blockade (ICB) targeting on PD-1/PD-L1 has shown remarkable promise in treating cancers. However, the low response rate and frequently observed severe side effects limit its broad benefits. It is partially due to less understanding of the biological regulation of PD-L1. Here, we systematically and comprehensively summarized the regulation of PD-L1 from nuclear chromatin reorganization to extracellular presentation. In PD-L1 and PD-L2 highly expressed cancer cells, a new TAD (topologically associating domain) (chr9: 5,400,000–5,600,000) around CD274 and CD273 was discovered, which includes a reported super-enhancer to drive synchronous transcription of PD-L1 and PD-L2. The re-shaped TAD allows transcription factors such as STAT3 and IRF1 recruit to PD-L1 locus in order to guide the expression of PD-L1. After transcription, the PD-L1 is tightly regulated by miRNAs and RNA-binding proteins via the long 3′UTR. At translational level, PD-L1 protein and its membrane presentation are tightly regulated by post-translational modification such as glycosylation and ubiquitination. In addition, PD-L1 can be secreted via exosome to systematically inhibit immune response. Therefore, fully dissecting the regulation of PD-L1/PD-L2 and thoroughly detecting PD-L1/PD-L2 as well as their regulatory networks will bring more insights in ICB and ICB-based combinational therapy. The level and characteristics of PD-L1/L2 in patients largely determine therapeutic efficacy to immune checkpoint blockade. PD-L1/L2 are precisely regulated and their characteristics are established by a complicated network. [Display omitted] [ABSTRACT FROM AUTHOR]

Epithelial to mesenchymal transition (EMT) is believed to be a principal factor contributing to cancer metastasis. The post-transcriptional and post-translational mechanisms underlying EMT are comparatively underexplored. We previously demonstrated that the CELF1 RNA binding protein is necessary and sufficient to drive the EMT of breast epithelial cells, and that the relative protein expression of CELF1 in this context was dictated at the post-translational level. Here, we elucidate the mechanism of this regulation. Mass spectrometric analysis of CELF1 isolated from mesenchymal MCF-10A cells identified multiple sites of serine and threonine phosphorylation on the protein, correlating with the increased stability of this protein in this cellular state. Analysis of phosphomimetic and serine/threonine-to-alanine phosphomutant variants of CELF1 revealed that these phosphorylation sites indeed dictate CELF1 stability, ubiquitination state, and function in vitro. Via co-immunoprecipitation and in vitro kinase assays, we identified the protein kinase C alpha and epsilon isozymes as the kinases responsible for CELF1 phosphorylation in a breast cell line. Genetic epistasis experiments confirmed that these PKCs function upstream of CELF1 in this EMT program, and CELF1 phosphorylation impacts tumor metastasis in a xenograft model. This work is the first to formally establish the mechanisms underlying post-translational control of CELF1 expression and function during EMT of breast epithelial cells. Given the broad dysregulation of CELF1 expression in human breast cancer, our results may ultimately provide knowledge that may be leveraged for novel therapeutic interventions in this context., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Post-transcriptional and post-translational modification of transcription factors (TFs) and pathway enzymes significantly affect the stress-stimulated biosynthesis of specialized metabolites (SM). Protein phosphorylation is one of the conserved and ancient mechanisms that critically influences many biological processes including specialized metabolism. The phosphorylation of TFs and enzymes by protein kinases (PKs), especially the Mitogen-Activated Protein Kinases (MAPKs), is well-studied in plants. While the roles of MAPKs in plant growth and development, phytohormone signaling, and immunity are well elucidated, significant recent advances have also been made in understanding the involvement of MAPKs in specialized metabolism. However, a comprehensive review highlighting the significant progress in the past several years is notably missing. This review focuses on MAPK-mediated regulation of several important SM, including phenylpropanoids (flavonoids and lignin), terpenoids (artemisinin and other terpenoids), alkaloids (terpenoid indole alkaloids and nicotine), and other nitrogen- and sulfur-containing SM (camalexin and indole glucosinolates). In addition to MAPKs, other PKs also regulate SM biosynthesis. For comparison, we briefly discuss the regulation by other PKs, such as sucrose non-fermenting-1 (SNF)-related protein kinases (SnRKs) and calcium-dependent protein kinases (CPKs). Furthermore, we provide future perspectives in this active area of research., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Microbiome interactions are important determinants for ecosystem functioning, stability, and health. In previous studies, it was often observed that bacteria suppress potentially pathogenic fungal species that are part of the same plant microbiota; however, the underlying microbe-microbe interplay remains mostly elusive. Here, we explored antagonistic interactions of the fungus Fusarium graminearum and bacterium Streptomyces hygroscopicus at the molecular level. Both are ubiquitous members of the healthy wheat microbiota; under dysbiosis, the fungus causes devastating diseases. Results: In co-cultures, we found that Streptomyces alters the fungal acetylome leading to substantial induction of fungal autophagy. The bacterium secrets rapamycin to inactivate the target of rapamycin (TOR), which subsequently promotes the degradation of the fungal histone acetyltransferase Gcn5 through the 26S proteasome. Gcn5 negatively regulates fungal autophagy by acetylating the autophagy-related protein Atg8 at the lysine site K13 and blocking cellular relocalization of Atg8. Thus, degradation of Gcn5 triggered by rapamycin was found to reduce Atg8 acetylation, resulting in autophagy induction in F. graminearum. Conclusions: Autophagy homeostasis plays an essential role in fungal growth and competition, as well as for virulence. Our work reveals a novel post-translational regulation of autophagy initiated by a bacterial antibiotic. Rapamycin was shown to be a powerful modulator of bacteria–fungi interactions with potential importance in explaining microbial homeostasis in healthy plant microbiomes. The autophagic process provides novel possibilities and targets to biologically control pathogens. 3Zu6EQMv78RbwrwJHF2G1T Video abstract [ABSTRACT FROM AUTHOR]

The reversible protein phosphorylation and dephosphorylation mediated by protein kinases and phosphatases regulate different biological processes and their response to environmental cues, including nitrogen (N) availability. Nitrate assimilation is under the strict control of phosphorylation—dephosphorylation mediated post-translational regulation. The protein phosphatase family with approximately 150 members in Arabidopsis and around 130 members in rice is a promising player in N uptake and assimilation pathways. Protein phosphatase 2A (PP2A) enhances the activation of nitrate reductase (NR) by deactivating SnRK1 and reduces the binding of inhibitory 14–3–3 proteins on NR. The functioning of nitrate transporter NPF6.3 is regulated by phosphorylation of CBL9 (Calcineurin B like protein 9) and CIPK23 (CBL interacting protein kinase 23) module. Phosphorylation by CIPK23 inhibits the activity of NPF6.3, whereas protein phosphatases (PP2C) enhance the NPF6.3-dependent nitrate sensing. PP2Cs and CIPK23 also regulate ammonium transporters (AMTs). Under either moderate ammonium supply or high N demand, CIPK23 is bound and inactivated by PP2Cs. Ammonium uptake is mediated by nonphosphorylated and active AMT1s. Whereas, under high ammonium availability, CIPK23 gets activated and phosphorylate AMT1;1 and AMT1;2 rendering them inactive. Recent reports suggest the critical role of protein phosphatases in regulating N use efficiency (NUE). In rice, PP2C9 regulates NUE by improving N uptake and assimilation. Comparative leaf proteome of wild type and PP2C9 over-expressing transgenic rice lines showed 30 differentially expressed proteins under low N level. These proteins are involved in photosynthesis, N metabolism, signalling, and defence. [ABSTRACT FROM AUTHOR]

SUMMARY: Chlorophyll (Chl) degradation is a natural phenomenon that occurs during ripening in many fleshy fruit species, and also during fruit storage. The plant hormone ethylene is a key factor in promoting Chl degradation during fruit storage, but the mechanisms involved in this induction are largely unknown. In this study, an apple (Malus domestica) BEL1‐LIKE HOMEODOMAIN transcription factor 7 (MdBEL7), potentially functioning as a transcriptional repressor of the Chl catabolic genes (CCGs), including MdCLH, MdPPH2 and MdRCCR2, was identified as a partner of the ethylene‐activated U‐box type E3 ubiquitin ligase MdPUB24 in a yeast library screen. Yeast‐two‐hybrid, co‐immunoprecipitation and luciferase complementation imaging assays were then used to verify the interaction between MdBEL7 and MdPUB24. In vitro and in vivo ubiquitination experiments revealed that MdPUB24 functions as an E3 ubiquitin ligase to ubiquitinate MdBEL7, thereby causing its degradation through the 26S proteasome pathway. Transient overexpression of MdPUB24 in apple fruit led to a decrease in MdBEL7 abundance and increased expression of CCG genes, including MdCLH, MdPPH2 and MdRCCR2, as well as greater Chl degradation. Taken together, the data indicated that an ethylene‐activated U‐box type E3 ubiquitin ligase MdPUB24 directly interacts with and ubiquitinates MdBEL7. Consequent degradation of MdBEL7 results in enhanced expression of MdCLH, MdPPH2 and MdRCCR2, and thus Chl degradation during apple fruit storage. Our results reveal that an ethylene‐MdPUB24‐MdBEL7 module regulates Chl degradation by post‐translational modification during apple fruit storage. Significance Statement: The ethylene‐activated U‐box type E3 ubiquitin ligase MdPUB24 from apple can directly interact with and ubiquitinate MdBEL7, leading to the degradation of the latter and enhanced expression of MdCLH, MdPPH2 and MdRCCR2, and thus can positively regulate chlorophyll degradation during apple fruit storage. This represents a regulatory module leading to enhancing Chl degradation during apple storage associated with a specific and pronounced post‐translational modification. [ABSTRACT FROM AUTHOR]

BACKGROUND: Myzus persicae (Sulzer), a worldwide pest, has caused remarkable damage to agriculture. Among the various control methods, chemical control (especially pyrethroids) is most commonly used. The targets of pyrethroids are voltage‐gated sodium channels (Navs). Unlike those of other insects, all Navs of aphids (including two genes), such as Myzus persicae, are unique. RESULTS: In this study, three interlock patterns, I(918)‐F(1014), L(918)‐L(1014), and T(918)‐F(1014), were found at sites 918 and 1014 in the sensitive Myzus persicae strain. Similar to that of other aphids, the Nav of Myzus persicae (MpNav) consisted of two parts, that is MpNav‐I and MpNav‐II, which were embedded with an atypical 'DENS' ion selectivity filter and a conventional 'MFM' inactivation gate, respectively. MpNav had 11 alternative exons, including two mutually exclusive exons (k and l) and three exons (w, x, and t), which were located in domains I and III, respectively. In addition, various RNA editing events, A503T and V588A, appearing between the connection of domains I and II and the S3 of domain IV, respectively, had been described. CONCLUSION: Overall, MpNav was characterized by unique post‐translational regulation mode, 918 and 1014 interlocks, and unusually alternative exons. Our research provides a new perspective on the evolution and variation of insect Navs. © 2021 Society of Chemical Industry [ABSTRACT FROM AUTHOR]

Matrix metalloproteinase-2 (a.k.a. Gelatinase A, or Mmp2 in zebrafish) is known to have roles in pathologies such as arthritis, in which its function is protective, as well as in cancer metastasis, in which it is activated as part of the migration and invasion of metastatic cells. It is also required during development and the regeneration of tissue architecture after wound healing, but its roles in tissue remodelling are not well understood. Gelatinase A is activated post-translationally by proteolytic cleavage, making information about its transcription and even patterns of protein accumulation difficult to relate to biologically relevant activity. Using a transgenic reporter of endogenous Mmp2 activation in zebrafish, we describe its accumulation and post-translational proteolytic activation during the embryonic development of the tail. Though Mmp2 is expressed relatively ubiquitously, it seems to be active only at specific locations and times. Mmp2 is activated robustly in the neural tube and in maturing myotome boundaries. It is also activated in the notochord during body axis straightening, in patches scattered throughout the epidermal epithelium, in the gut, and on cellular protrusions extending from mesenchymal cells in the fin folds. The activation of Mmp2 in the notochord, somite boundaries and fin folds associates with collagen remodelling in the notochord sheath, myotome boundary ECM and actinotrichia respectively. Mmp2 is likely an important effector of ECM remodelling during the morphogenesis of the notochord, a driving structure in vertebrate development. It also appears to function in remodelling the ECM associated with growing epithelia and the maturation of actinotrichia in the fin folds, mediated by mesenchymal cell podosomes. [Display omitted] • Visualization of the post-translational proteolytic activation of Matrix Metalloproteinase 2 (Mmp2) in the intact zebrafish embryo using a novel transgenic reporter reveals strong activation in • maturing somite boundaries • associated with notochord elongation • in the developing gut and hematopoietic tissues • in a patchwork pattern in the epidermis • associated with invadopodia-like podosomes in the developing fin folds • Activation of Mmp2 correlates with patterns of collagen denaturation detected using a collagen hybridizing peptide. • Mesenchymal cells associated with actinotrichia in the fin folds accumulate in-active proMmp2. [ABSTRACT FROM AUTHOR]

Abstract Background Analysis of high-throughput multi-’omics interactions across the hierarchy of expression has wide interest in making inferences with regard to biological function and biomarker discovery. Expression levels across different scales are determined by robust synthesis, regulation and degradation processes, and hence transcript (mRNA) measurements made by microarray/RNA-Seq only show modest correlation with corresponding protein levels. Results In this work we are interested in quantitative modelling of correlation across such gene products. Building on recent work, we develop computational models spanning transcript, translation and protein levels at different stages of the H. sapiens cell cycle. We enhance this analysis by incorporating 25+ sequence-derived features which are likely determinants of cellular protein concentration and quantitatively select for relevant features, producing a vast dataset with thousands of genes. We reveal insights into the complex interplay between expression levels across time, using machine learning methods to highlight outliers with respect to such models as proteins associated with post-translationally regulated modes of action. Conclusions We uncover quantitative separation between modified and degraded proteins that have roles in cell cycle regulation, chromatin remodelling and protein catabolism according to Gene Ontology; and highlight the opportunities for providing biological insights in future model systems.

Regulatory T (Treg) cells are indispensable for immune homeostasis due to their roles in peripheral tolerance. As the master transcription factor of Treg cells, Forkhead box P3 (Foxp3) strongly regulates Treg function and plasticity. Because of this, considerable research efforts have been directed at elucidating the mechanisms controlling Foxp3 and its co-regulators. Such work is not only advancing our understanding on Treg cell biology, but also uncovering novel targets for clinical manipulation in autoimmune diseases, organ transplantation, and tumor therapies. Recently, many studies have explored the post-translational regulation of Foxp3, which have shown that acetylation, phosphorylation, glycosylation, methylation, and ubiquitination are important for determining Foxp3 function and plasticity. Additionally, some of these targets have been implicated to have great therapeutic values. In this review, we will discuss emerging evidence of post-translational regulations on Foxp3 in Treg cells and their exciting therapeutic applications.

Phenolic acids are the major secondary metabolites and significant bioactive constituents of the medicinal plant Salvia miltiorrhiza. Many enzyme-encoding genes and transcription factors involved in the biosynthesis of phenolic acids have been identified, but the underlying post-translational regulatory mechanisms are poorly understood. Here, we demonstrate that the S. miltiorrhiza Kelch repeat F-box protein SmKFB5 physically interacts with three phenylalanine ammonia-lyase (PAL) isozymes and mediates their proteolytic turnover via the ubiquitin-26S proteasome pathway. Disturbing the expression of SmKFB5 reciprocally affected the abundance of SmPAL protein and the accumulation of phenolic acids, suggesting that SmKFB5 is a post-translational regulator responsible for the turnover of PAL and negatively controlling phenolic acids. Furthermore, we discovered that treatment of the hairy root of S. miltiorrhiza with methyl jasmonate suppressed the expression of SmKFB5 while inducing the transcription of SmPAL1 and SmPAL3. These data suggested that methyl jasmonate consolidated both transcriptional and post-translational regulation mechanisms to enhance phenolic acid biosynthesis. Taken together, our results provide insights into the molecular mechanisms by which SmKFB5 mediates the regulation of phenolic acid biosynthesis by jasmonic acid, and suggest valuable targets for plant breeders in tailoring new cultivars. [ABSTRACT FROM AUTHOR]

Chlorophyll (Chl) is indispensable for photosynthesis. In association with Chl-binding proteins (CBPs), it is responsible for light absorption, excitation energy transfer, and charge separation within the photosynthetic complexes. By contrast, photoexcitation of free Chl and its metabolic intermediates generates hazardous reactive oxygen species (ROS). While antagonistic activities of Chl synthesis and catabolism have been mostly elucidated, the tight synchronization of these metabolic activities with the formation and dismantling of the photosynthetic complexes is poorly understood. Recently, a set of auxiliary factors were identified to adjust metabolic activities and provide accurate amounts of Chl for pigment–protein complexes. Here, we review current knowledge of post-translational coordination of Chl formation, breakdown, and turnover with the assembly and disassembly of various CBPs and highlight future research perspectives. Optimal photosynthesis and proper leaf development rely on spatiotemporal regulation of Chl metabolism. Availability of Chl is crucial for the stability, correct folding, and membrane integration of CBPs; and Chl release occurs before the proteolysis of Chl-binding proteins. A conserved Chl assembly complex identified in arabidopsis (Arabidopsis thaliana) and cyanobacteria requires auxiliary factors, which may function either as Chl carriers or scaffold proteins that facilitate the integration of Chl into CBPs at the thylakoid membranes. A suite of post-translational regulators is implicated in the regulation of various aspects of Chl metabolism, and serve to coordinate the varying demand for Chl for biogenesis, maintenance, and degradation of the pigment–protein complexes. [ABSTRACT FROM AUTHOR]

Regulatory T (Treg) cells are indispensable for immune homeostasis due to their roles in peripheral tolerance. As the master transcription factor of Treg cells, Forkhead box P3 (Foxp3) strongly regulates Treg function and plasticity. Because of this, considerable research efforts have been directed at elucidating the mechanisms controlling Foxp3 and its co-regulators. Such work is not only advancing our understanding on Treg cell biology, but also uncovering novel targets for clinical manipulation in autoimmune diseases, organ transplantation, and tumor therapies. Recently, many studies have explored the post-translational regulation of Foxp3, which have shown that acetylation, phosphorylation, glycosylation, methylation, and ubiquitination are important for determining Foxp3 function and plasticity. Additionally, some of these targets have been implicated to have great therapeutic values. In this review, we will discuss emerging evidence of post-translational regulations on Foxp3 in Treg cells and their exciting therapeutic applications. [ABSTRACT FROM AUTHOR]

Forkhead box transcription factor, FOXM1 is implicated in several cellular processes such as proliferation, cell cycle progression, cell differentiation, DNA damage repair, tissue homeostasis, angiogenesis, apoptosis, and redox signaling. In addition to being a boon for the normal functioning of a cell, FOXM1 turns out to be a bane by manifesting in several disease scenarios including cancer. It has been given an oncogenic status based on several evidences indicating its role in tumor development and progression. FOXM1 is highly expressed in several cancers and has also been implicated in poor prognosis. A comprehensive understanding of various aspects of this molecule has revealed its role in angiogenesis, invasion, migration, self- renewal and drug resistance. In this review, we attempt to understand various mechanisms underlying FOXM1 gene and protein regulation in cancer including the different signaling pathways, post-transcriptional and post-translational modifications. Identifying crucial molecules associated with these processes can aid in the development of potential pharmacological approaches to curb FOXM1 mediated tumorigenesis.