10 results on '"Ying, Li"'
Search Results
2. CD38 produces nicotinic acid adenosine dinucleotide phosphate in the lysosome
- Author
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Qi Wen Deng, Ya Jie Chen, Cheng Fang, Ting Li, Yun Nan Hou, Ying Li, Hon Cheung Lee, Yong Juan Zhao, and Guan Jie Xu
- Subjects
0301 basic medicine ,030102 biochemistry & molecular biology ,Chemistry ,media_common.quotation_subject ,hemic and immune systems ,Cell Biology ,Endocytosis ,Biochemistry ,Endolysosome ,Cell biology ,03 medical and health sciences ,Enzyme activator ,030104 developmental biology ,medicine.anatomical_structure ,immune system diseases ,hemic and lymphatic diseases ,Lysosome ,Second messenger system ,medicine ,Internalization ,Molecular Biology ,Intracellular ,media_common ,Calcium signaling - Abstract
Nicotinic acid adenosine dinucleotide phosphate (NAADP) is a Ca2+-mobilizing second messenger that regulates a wide range of biological activities. However, the mechanism of its biogenesis remains controversial. CD38 is the only enzyme known to catalyze NAADP synthesis from NADP and nicotinic acid. CD38-mediated catalysis requires an acidic pH, suggesting that NAADP may be produced in acidic endolysosomes, but this hypothesis is untested. In this study, using human cell lines, we specifically directed CD38 to the endolysosomal system and assessed cellular NAADP production. First, we found that nanobodies targeting various epitopes on the C-terminal domain of CD38 could bind to cell surface–localized CD38 and induce its endocytosis. We also found that CD38 internalization occurred via a clathrin-dependent pathway, delivered CD38 to the endolysosome, and elevated intracellular NAADP levels. We also created a CD38 variant for lysosome-specific expression, which not only withstood the degradative environment in the lysosome, but was also much more active than WT CD38 in elevating cellular NAADP levels. Supplementing CD38-expressing cells with nicotinic acid substantially increased cellular NAADP levels. These results demonstrate that endolysosomal CD38 can produce NAADP in human cells. They further suggest that CD38's compartmentalization to the lysosome may allow for its regulation via substrate access, rather than enzyme activation, thereby providing a reliable mechanism for regulating cellular NAADP production.
- Published
- 2018
3. TFEB insufficiency promotes cardiac hypertrophy by blocking autophagic degradation of GATA4
- Author
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Rui Song, Han Lei, Wanwen Cheng, Ling Ling Yao, Li Feng, Jie Liu, and Ying Li
- Subjects
Autophagosome ,TF, transcription factor ,LVIDd, diastolic LV internal dimension ,CQ, chloroquine ,ATG7, autophagy-related protein 7 ,mTORC1 ,HF, heart failure ,Biochemistry ,Muscle hypertrophy ,Mice ,RFP, red fluorescent protein ,AAV, adeno-associated virus ,Medicine ,Myocytes, Cardiac ,TFEB, transcription factor EB ,MOI, multiplicity of infection ,FS, fractional shortening ,Basic Helix-Loop-Helix Leucine Zipper Transcription Factors ,BW, body weight ,BafA1, bafilomycin A1 ,IP, immunoprecipitation ,mTORC1, mechanistic target of rapamycin kinase complex 1 ,NPPB, natriuretic peptide precursor B ,Cell biology ,LVIDs, systolic LV internal dimension ,cardiovascular system ,β-MHC, myosin heavy chain-β ,TAC, transverse aortic constriction ,hypertrophy ,Research Article ,autophagy ,NRVM, neonatal rat ventricular myocyte ,WGA, wheat germ agglutinin ,Cardiomegaly ,NIH, the National Institutes of Health ,heart ,MYH7B, myosin heavy chain 7B ,ALP, autophagosome–lysosome pathway ,GATA4 ,Downregulation and upregulation ,Animals ,Humans ,EF, ejection fraction ,PO, pressure overload ,Autophagy-Related Protein 7 ,ANP, atrial natriuretic peptide ,LV, left ventricular ,Molecular Biology ,PGC1α, peroxisome proliferator–activated receptor-gamma coactivator-1α ,KD, knockdown ,Pressure overload ,TFEB ,PE, phenylephrine ,autophagosome–lysosome pathway ,business.industry ,Autophagy ,Cell Biology ,NPPA, natriuretic peptide precursor A ,GATA4 Transcription Factor ,LC3, light chain 3 ,Proteolysis ,business - Abstract
Autophagosome–lysosome pathway (ALP) insufficiency has been suggested to play a critical role in the pathogenesis of cardiac hypertrophy. However, the mechanisms underlying ALP insufficiency remain largely unknown, and strategies to specifically manipulate ALP insufficiency for treating cardiac hypertrophy are lacking. Transcription factor EB (TFEB), as a master regulator of ALP, regulates the generation and function of autophagosomes and lysosomes. We found that TFEB was significantly decreased, whereas autophagosome markers were increased in phenylephrine (PE)-induced and transverse aortic constriction–induced cardiomyocyte hypertrophy and failing hearts from patients with dilated cardiomyopathy. Knocking down TFEB induced ALP insufficiency, as indicated by increased autophagosome markers, decreased light chain 3II flux, and cardiomyocyte hypertrophy manifested through increased levels of atrial natriuretic peptide and β-myosin heavy chain and enlarged cell size. The effects of TFEB knockdown were abolished by promoting autophagy. TFEB overexpression improved autophagic flux and attenuated PE-stimulated cardiomyocyte hypertrophy and transverse aortic constriction–induced hypertrophic remodeling, fibrosis, and cardiac dysfunction. Curcumin analog compound C1, a specific TFEB activator, similarly attenuated PE-induced ALP insufficiency and cardiomyocyte hypertrophy. TFEB knockdown increased the accumulation of GATA4, a transcription factor for several genes causing cardiac hypertrophy by blocking autophagic degradation of GATA4, whereas knocking down GATA4 attenuated TFEB downregulation–induced cardiomyocyte hypertrophy. Both TFEB overexpression and C1 promoted GATA4 autophagic degradation and alleviated PE-induced cardiomyocyte hypertrophy. In conclusion, TFEB downregulation plays a vital role in the development of pressure overload–induced cardiac hypertrophy by causing ALP insufficiency and blocking autophagic degradation. Activation of TFEB represents a potential therapeutic strategy for treating cardiac hypertrophy.
- Published
- 2021
4. Correction: CD38 produces nicotinic acid adenine dinucleotide phosphate in the lysosome
- Author
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Yun Nan Hou, Qi Wen Deng, Yong Juan Zhao, Cheng Fang, Ying Li, Hon Cheung Lee, Ting Li, Ya Jie Chen, and Guan Jie Xu
- Subjects
Vasodilator Agents ,CD38 ,Niacin ,Biochemistry ,chemistry.chemical_compound ,immune system diseases ,hemic and lymphatic diseases ,Lysosome ,medicine ,Humans ,Calcium Signaling ,Molecular Biology ,Membrane Glycoproteins ,Nicotinic acid adenine dinucleotide phosphate ,hemic and immune systems ,Cell Biology ,Single-Domain Antibodies ,ADP-ribosyl Cyclase 1 ,Endocytosis ,HEK293 Cells ,medicine.anatomical_structure ,chemistry ,Additions and Corrections ,Calcium ,Lysosomes ,NADP ,HeLa Cells - Abstract
Nicotinic acid adenosine dinucleotide phosphate (NAADP) is a Ca(2+)-mobilizing second messenger that regulates a wide range of biological activities. However, the mechanism of its biogenesis remains controversial. CD38 is the only enzyme known to catalyze NAADP synthesis from NADP and nicotinic acid. CD38-mediated catalysis requires an acidic pH, suggesting that NAADP may be produced in acidic endolysosomes, but this hypothesis is untested. In this study, using human cell lines, we specifically directed CD38 to the endolysosomal system and assessed cellular NAADP production. First, we found that nanobodies targeting various epitopes on the C-terminal domain of CD38 could bind to cell surface–localized CD38 and induce its endocytosis. We also found that CD38 internalization occurred via a clathrin-dependent pathway, delivered CD38 to the endolysosome, and elevated intracellular NAADP levels. We also created a CD38 variant for lysosome-specific expression, which not only withstood the degradative environment in the lysosome, but was also much more active than WT CD38 in elevating cellular NAADP levels. Supplementing CD38-expressing cells with nicotinic acid substantially increased cellular NAADP levels. These results demonstrate that endolysosomal CD38 can produce NAADP in human cells. They further suggest that CD38's compartmentalization to the lysosome may allow for its regulation via substrate access, rather than enzyme activation, thereby providing a reliable mechanism for regulating cellular NAADP production.
- Published
- 2019
5. Dihydroceramides: From Bit Players to Lead Actors
- Author
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Monowarul Mobin Siddique, Scott A. Summers, Ying Li, Bhagirath Chaurasia, and Vincent A. Kaddai
- Subjects
Cell signaling ,Autophagy ,Neurodegenerative Diseases ,Minireviews ,Cell Biology ,Biology ,Ceramides ,Biochemistry ,Sphingolipid ,Sphingomyelins ,Sphingolipid synthesis ,Apoptosis ,Neoplasms ,Reperfusion Injury ,Diabetes Mellitus ,Animals ,Humans ,lipids (amino acids, peptides, and proteins) ,Sphingomyelin ,Molecular Biology ,Glucosylceramides ,Cell Proliferation - Abstract
Sphingolipid synthesis involves a highly conserved biosynthetic pathway that produces fundamental precursors of complex sphingolipids. The final reaction involves the insertion of a double bond into dihydroceramides to generate the more abundant ceramides, which are converted to sphingomyelins and glucosylceramides/gangliosides by the addition of polar head groups. Although ceramides have long been known to mediate cellular stress responses, the dihydroceramides that are transiently produced during de novo sphingolipid synthesis were deemed inert. Evidence published in the last few years suggests that these dihydroceramides accumulate to a far greater extent in tissues than previously thought. Moreover, they have biological functions that are distinct and non-overlapping with those of the more prevalent ceramides. Roles are being uncovered in autophagy, hypoxia, and cellular proliferation, and the lipids are now implicated in the etiology, treatment, and/or diagnosis of diabetes, cancer, ischemia/reperfusion injury, and neurodegenerative diseases. This minireview summarizes recent findings on this emerging class of bioactive lipids.
- Published
- 2015
6. Dihydroceramides: From Bit Players to Lead Actors.
- Author
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Siddique, Monowarul Mobin, Ying Li, Chaurasia, Bhagirath, Kaddai, Vincent A., and Summers, Scott A.
- Subjects
- *
SPHINGOLIPIDS , *BIOSYNTHESIS , *CERAMIDES , *SPHINGOMYELIN , *GANGLIOSIDES , *DOUBLE bonds - Abstract
Sphingolipid synthesis involves a highly conserved biosynthetic pathway that produces fundamental precursors of complex sphingolipids. The final reaction involves the insertion of a double bond into dihydroceramides to generate the more abundant ceramides, which are converted to sphingomyelins and glucosylceramides/gangliosides by the addition of polar head groups. Although ceramides have long been known to mediate cellular stress responses, the dihydroceramides that are transiently produced during de novo sphingolipid synthesis were deemed inert. Evidence published in the last few years suggests that these dihydroceramides accumulate to a far greater extent in tissues than previously thought. Moreover, they have biological functions that are distinct and non-overlapping with those of the more prevalent ceramides. Roles are being uncovered in autophagy, hypoxia, and cellular proliferation, and the lipids are now implicated in the etiology, treatment, and/or diagnosis of diabetes, cancer, ischemia/ reperfusion injury, and neurodegenerative diseases. This minireview summarizes recent findings on this emerging class of bioactive lipids. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
7. Modulation of conformational equilibrium by phosphorylation underlies the activation of deubiquitinase A.
- Author
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Kabra, Ashish, Rumpa, Efsita, and Ying Li
- Subjects
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POST-translational modification , *UBIQUITINATION , *TYPE I interferons , *DEPHOSPHORYLATION , *PHOSPHORYLATION , *ENZYME kinetics , *NUCLEAR magnetic resonance spectroscopy , *EQUILIBRIUM - Abstract
Deubiquitinases deconjugate ubiquitin modifications from target proteins and are involved in many cellular processes in eukaryotes. The functions of deubiquitinases are regulated by post-translational modifications, mainly phosphorylation and ubiquitination. Post-translational modifications can result in subtle changes in structural and dynamic properties, which are difficult to identify but functionally important. In this work, we used NMR spectroscopy to characterize the conformational properties of the human deubiquitinase A (DUBA), a negative regulator of type I interferon. DUBA activity is regulated by phosphorylation at a single serine residue, Ser-177. We found that the catalytic rate constant of DUBA is enhanced by phosphorylation. By comparing NMR and enzyme kinetics data among different forms of DUBA with low and high activities, we concluded that a two-state equilibrium that was present only in phosphorylated DUBA is important for DUBA activity. Our results highlight the importance of defining conformational dynamics in understanding the mechanism of DUBA activation. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
8. CD38 produces nicotinic acid adenosine dinucleotide phosphate in the lysosome.
- Author
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Cheng Fang, Ting Li, Ying Li, Guan Jie Xu, Qi Wen Deng, Ya Jie Chen, Yun Nan Hou, Hon Cheung Lee, and Yong Juan Zhao
- Subjects
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CD38 antigen , *NICOTINIC acid adenine dinucleotide phosphate , *LYSOSOMES , *CATALYSIS , *ENZYME analysis - Abstract
Nicotinic acid adenosine dinucleotide phosphate (NAADP) is aCa2+-mobilizing second messenger that regulates a wide range of biological activities. However, the mechanism of its biogenesis remains controversial. CD38 is the only enzyme known to catalyze NAADP synthesis from NADP and nicotinic acid. CD38-mediated catalysis requires an acidic pH, suggesting that NAADP may be produced in acidic endolysosomes, but this hypothesis is untested. In this study, using human cell lines, we specifically directed CD38 to the endolysosomal system and assessed cellularNAADPproduction. First, we found that nanobodies targeting various epitopes on the C-terminal domain of CD38 could bind to cell surface-localized CD38 and induce its endocytosis. We also found that CD38 internalization occurred via a clathrin-dependent pathway, delivered CD38 to the endolysosome, and elevated intracellular NAADP levels. We also created a CD38 variant for lysosome-specific expression, which not only withstood the degradative environment in the lysosome, but was also much more active than WT CD38 in elevating cellular NAADP levels. Supplementing CD38-expressing cells with nicotinic acid substantially increased cellular NAADP levels. These results demonstrate that endolysosomal CD38 can produceNAADPin human cells. They further suggest that CD38's compartmentalization to the lysosome may allow for its regulation via substrate access, rather than enzyme activation, thereby providing a reliable mechanism for regulating cellular NAADP production. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
9. Identification and characterization of a novel hydroxylamine oxidase, DnfA, that catalyzes the oxidation of hydroxylamine to N2.
- Author
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Meng-Ru Wu, Li-Li Miao, Ying Liu, Xin-Xin Qian, Ting-Ting Hou, Guo-Min Ai, Lu Yu, Lan Ma, Xi-Yan Gao, Ya-Ling Qin, Hai-Zhen Zhu, Lei Du, Sheng-Ying Li, Chang-Lin Tian, De-Feng Li, Zhi-Pei Liu, and Shuang-Jiang Liu
- Subjects
- *
HYDROXYLAMINE , *ELECTRON paramagnetic resonance , *OXIDATION-reduction reaction , *NITROGEN , *ENZYME kinetics , *OXIDATION , *NITROGEN removal (Water purification) - Abstract
Nitrogen (N2) gas in the atmosphere is partially replenished by microbial denitrification of ammonia. Recent study has shown that Alcaligenes ammonioxydans oxidizes ammonia to dinitrogen via a process featuring the intermediate hydroxylamine, termed "Dirammox" (direct ammonia oxidation). However, the unique biochemistry of this process remains unknown. Here, we report an enzyme involved in Dirammox that catalyzes the conversion of hydroxylamine to N2. We tested previously annotated proteins involved in redox reactions, DnfA, DnfB, and DnfC, to determine their ability to catalyze the oxidation of ammonia or hydroxylamine. Our results showed that none of these proteins bound to ammonia or catalyzed its oxidation; however, we did find DnfA bound to hydroxylamine. Further experiments demonstrated that, in the presence of NADH and FAD, DnfA catalyzed the conversion of 15N-labeled hydroxylamine to 15N2. This conversion did not happen under oxygen (O2)-free conditions. Thus, we concluded that DnfA encodes a hydroxylamine oxidase. We demonstrate that DnfA is not homologous to any known hydroxylamine oxidoreductases and contains a diiron center, which was shown to be involved in catalysis via electron paramagnetic resonance experiments. Furthermore, enzyme kinetics of DnfA were assayed, revealing a Km of 92.9 ± 3.0 μM for hydroxylamine and a kcat of 0.028 ± 0.001 s-1. Finally, we show that DnfA was localized in the cytoplasm and periplasm as well as in tubular membrane invaginations in HO-1 cells. To the best of our knowledge, we conclude that DnfA is the first enzyme discovered that catalyzes oxidation of hydroxylamine to N2. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
10. Toll-like receptor 4-induced ryanodine receptor 2 oxidation and sarcoplasmic reticulum Ca2+ leakage promote cardiac contractile dysfunction in sepsis.
- Author
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Jie Yang, Rui Zhang, Xin Jiang, Jingzhang Lv, Ying Li, Hongyu Ye, Wenjuan Liu, Gang Wang, Cuicui Zhang, Na Zheng, Ming Dong, Yan Wang, Peiya Chen, Santosh, Kumar, Yong Jiang, and Jie Liu
- Subjects
- *
RYANODINE receptors , *TOLL-like receptors , *OXIDATION , *SEPSIS , *CARDIAC contraction , *SARCOPLASMIC reticulum - Abstract
Studies suggest the potential role of a sarcoplasmic reticulum (SR) Ca2+ leak in cardiac contractile dysfunction in sepsis. However, direct supporting evidence is lacking, and the mechanisms underlying this SR leak are poorly understood. Here, we investigated the changes in cardiac Ca2+ handling and contraction in LPS-treated rat cardiomyocytes and a mouse model of polymicrobial sepsis produced by cecal ligation and puncture (CLP). LPS decreased the systolic Ca2+ transient and myocyte contraction as well as SR Ca2+ content. Meanwhile, LPS increased Ca2+ spark-mediated SR Ca2+leak. Preventing the SR leak with ryanodine receptor (RyR) blocker tetracaine restored SR load and increased myocyte contraction. Similar alterations in Ca2+ handling were observed in cardiomyocytes from CLP mice. Treatment with JTV-519, an anti-SR leak drug, restored Ca2+ handling and improved cardiac function. In the LPS-treated cardiomyocytes, mitochondrial reactive oxygen species and oxidative stress in RyR2 were increased, whereas the levels of the RyR2-associated FK506-binding protein 1B (FKBP12.6) were decreased. The Toll-like receptor 4 (TLR4)-specific inhibitor TAK-242 reduced the oxidative stress in LPS-treated cells, decreased the SR leak, and normalized Ca2+ handling and myocyte contraction. Consistently, TLR4 deletion significantly improved cardiac function and corrected abnormal Ca2+ handling in the CLP mice. This study provides evidence for the critical role of the SR Ca2+ leak in the development of septic cardiomyopathy and highlights the therapeutic potential of JTV-519 by preventing SR leak. Furthermore, it reveals that TLR4 activation-induced mitochondrial reactive oxygen species production and the resulting oxidative stress in RyR2 contribute to the SR Ca2+ leak. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
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