Site-specific ubiquitination of VDAC1 restricts its oligomerization and mitochondrial DNA release in liver fibrosis
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Mitochondrial DNA (mtDNA) released through protein oligomers, such as voltage-dependent anion channel 1 (VDAC1), triggers innate immune activation and thus contributes to liver fibrosis. Here, we investigated the role of Parkin, an important regulator of mitochondria, and its regulation of VDAC1-mediated mtDNA release in liver fibrosis. The circulating mitochondrial DNA (mtDNA) and protein levels of liver Parkin and VDAC1 were upregulated in patients with liver fibrosis. A 4-week CCl4 challenge induced release of mtDNA, activation of STING signaling, a decline in autophagy, and apoptosis in mouse livers, and the knockout of Parkin aggravated these effects. In addition, Parkin reduced mtDNA release and prevented VDAC1 oligomerization in a manner dependent on its E3 activity in hepatocytes. We found that site-specific ubiquitination of VDAC1 at lysine 53 by Parkin interrupted VDAC1 oligomerization and prevented mtDNA release into the cytoplasm under stress. The ubiquitination-defective VDAC1 K53R mutant predominantly formed oligomers that resisted suppression by Parkin. Hepatocytes expressing VDAC1 K53R exhibited mtDNA release and thus activated the STING signaling pathway in hepatic stellate cells, and this effect could not be abolished by Parkin. We propose that the ubiquitination of VDAC1 at a specific site by Parkin confers protection against liver fibrosis by interrupting VDAC1 oligomerization and mtDNA release.
Abstract
Mitochondrial DNA (mtDNA) released through protein oligomers, such as voltage-dependent anion channel 1 (VDAC1), triggers innate immune activation and thus contributes to liver fibrosis. Here, we investigated the role of Parkin, an important regulator of mitochondria, and its regulation of VDAC1-mediated mtDNA release in liver fibrosis. The circulating mitochondrial DNA (mtDNA) and protein levels of liver Parkin and VDAC1 were upregulated in patients with liver fibrosis. A 4-week CCl4 challenge induced release of mtDNA, activation of STING signaling, a decline in autophagy, and apoptosis in mouse livers, and the knockout of Parkin aggravated these effects. In addition, Parkin reduced mtDNA release and prevented VDAC1 oligomerization in a manner dependent on its E3 activity in hepatocytes. We found that site-specific ubiquitination of VDAC1 at lysine 53 by Parkin interrupted VDAC1 oligomerization and prevented mtDNA release into the cytoplasm under stress. The ubiquitination-defective VDAC1 K53R mutant predominantly formed oligomers that resisted suppression by Parkin. Hepatocytes expressing VDAC1 K53R exhibited mtDNA release and thus activated the STING signaling pathway in hepatic stellate cells, and this effect could not be abolished by Parkin. We propose that the ubiquitination of VDAC1 at a specific site by Parkin confers protection against liver fibrosis by interrupting VDAC1 oligomerization and mtDNA release.
참고문헌 (40)
- Iracheta-Vellve, A., "Endoplasmic Reticulum Stress-induced Hepatocellular Death Pathways Mediate Liver Injury and Fibrosis via Stimulator of Interferon Genes", J. Biol. Chem, 291, pp.26794~26805 (2016)
- Luo, X., "Expression of STING Is Increased in Liver Tissues From Patients With NAFLD and Promotes Macrophage-Mediated Hepatic Inflammation and Fibrosis in Mice", Gastroenterology, 155, pp.1971~1984 (2018)
- An, P., "Hepatocyte mitochondria-derived danger signals directly activate hepatic stellate cells and drive progression of liver fibrosis", Nat. Commun, 11, pp.2362~ (2020)
- Brenner, C., "Decoding cell death signals in liver inflammation", J. Hepatol, 59, pp.583~594 (2013)
- Mills, E. L., "Mitochondria are the powerhouses of immunity", Nat. Immunol, 18, pp.488~498 (2017)
- West, A. P., "Mitochondrial DNA stress primes the antiviral innate immune response", Nature, 520, pp.553~557 (2015)
- Kang, J. W., "Melatonin enhances mitophagy and mitochondrial biogenesis in rats with carbon tetrachloride-induced liver fibrosis", J. Pineal Res, 60, pp.383~393 (2016)
- Zhao, Y., "p66Shc Contributes to Liver Fibrosis through the Regulation of Mitochondrial Reactive Oxygen Species", Theranostics, 9, pp.1510~1522 (2019)
- Garcia-Martinez, I., "Hepatocyte mitochondrial DNA drives nonalcoholic steatohepatitis by activation of TLR9", J. Clin. Invest, 126, pp.859~864 (2016)
- West, A. P., "Mitochondrial DNA in innate immune responses and inflammatory pathology", Nat. Rev. Immunol, 17, pp.363~375 (2017)
- Deretic, V., "Autophagy in inflammation, infection, and immunometabolism", Immunity, 54, pp.437~453 (2021)
- Wu, N. N., "Mitophagy, Mitochondrial Dynamics, and Homeostasis in Cardiovascular Aging", Oxid. Med. Cell. Longev, 2019, pp.9825061~ (2019)
- Sliter, D. A., "Parkin and PINK1 mitigate STING-induced inflammation", Nature, 561, pp.258~262 (2018)
- Kim, J., "VDAC oligomers form mitochondrial pores to release mtDNA fragments and promote lupus-like disease", Science, 366, pp.1531~1536 (2019)
- McArthur, K., "BAK", BAX macropores facilitate mitochondrial herniation and mtDNA efflux during apoptosis, 2018, pp.359, eaao6047~
- Bernardini, J. P., "Parkin inhibits BAK and BAX apoptotic function by distinct mechanisms during mitophagy", EMBO J, 38, pp.e99916~ (2019)
- Saijou, E., "Neutrophils alleviate fibrosis in the CCl(4)-induced mouse chronic liver injury model", Hepatol. Commun, 2, pp.703~717 (2018)
- Guo, R., "Aldehyde dedydrogenase-2plays a beneficial role in ameliorating chronic alcohol-induced hepatic steatosis and inflammation through regulation of autophagy", J. Hepatol, 62, pp.647~656 (2015)
- Ajaz, S., "Accurate measurement of circulating mitochondrial DNA content from human blood samples using real-time quantitative PCR", Methods Mol. Biol, 1264, pp.117~131 (2015)
- Wang, S., "Ablation of Akt2 and AMPKα2 rescues high fat diet-induced obesity and hepatic steatosis through Parkin-mediated mitophagy", Acta Pharm. Sin. B, 11, pp.3508~3526 (2021)
- Xu, H., "TAX1BP1 protects against myocardial infarction-associated cardiac anomalies through inhibition of inflammasomes in a RNF34", MAVS, Sci. Bull, pp.2021, 66[DOI]
- Ren, J., "FUNDC1 interacts with FBXL2 to govern mitochondrial integrity and cardiac function through an IP3R3-dependent manner in obesity", Sci. Adv, 6, pp.eabc8561~ (2020)
- Yang, M., "Deletion of the E3 ubiquitin ligase, Parkin, exacerbates chronic alcohol intake-induced cardiomyopathy through an Ambra1-dependent mechanism", Br. J. Pharmacol, 178, pp.964~982 (2021)
- Hernandez-Gea, V., "Co-expression gene network analysis reveals novel regulatory pathways involved in porto-sinusoidal vascular disease", J. Hepatol, 75, pp.924~934 (2021)
- Love, M. I., "Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2", Genome Biol, 15, pp.550~ (2014)
- Yu, G., "clusterProfiler: an R package for comparing biological themes among gene clusters", Omics, 16, pp.284~287 (2012)
- Schoggins, J. W., "Pan-viral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity", Nature, 505, pp.691~695 (2014)
- Barcena, C., "Angiogenin secretion from hepatoma cells activates hepatic stellate cells to amplify a self-sustained cycle promoting liver cancer", Sci. Rep, 5, pp.7916~ (2015)
- Yuan, W. -C., "K33-Linked Polyubiquitination of Coronin 7 by Cul3-KLHL20 Ubiquitin E3 Ligase Regulates Protein Trafficking", Mol. Cell, 54, pp.586~600 (2014)
- Wang, S., "ALDH2 contributes to melatonin-induced protection against APP", PS1 mutation-prompted cardiac anomalies through cGAS-STING-TBK1-mediated regulation of mitophagy, 2020, pp.5, 119~
- Nagakannan, P., "Inhibition of VDAC1 Protects Against Glutamate-Induced Oxytosis and Mitochondrial Fragmentation in Hippocampal HT22 Cells", Cell Mol. Neurobiol, 39, pp.73~85 (2019)
- Ajoolabady, A., "Mitophagy Receptors and Mediators : Therapeutic Targets in the Management of Cardiovascular Ageing", Ageing Res. Rev, 62, pp.101129~ (2020)
- Lin, X. H., "Suppressing DRP1-mediated mitochondrial fission and mitophagy increases mitochondrial apoptosis of hepatocellular carcinoma cells in the setting of hypoxia", Oncogenesis, 9, pp.67~ (2020)
- Abu-Hamad, S., "The VDAC1 N-terminus is essential both for apoptosis and the protective effect of anti-apoptotic proteins", J. Cell Sci, 122, pp.1906~1916 (2009)
- Ordureau, A., "Dynamics of PARKIN-Dependent Mitochondrial Ubiquitylation in Induced Neurons and Model Systems Revealed by Digital Snapshot Proteomics", Mol. Cell, 70, pp.211~227 (2018)
- Petrasek, J., "STING-IRF3 pathway links endoplasmic reticulum stress with hepatocyte apoptosis in early alcoholic liver disease", Proc. Natl Acad. Sci. U. S. A, 110, pp.16544~16549 (2013)
- Ham, S. J., "Decision between mitophagy and apoptosis by Parkin via VDAC1ubiquitination", Proc. Natl Acad. Sci. U. S. A, 117, pp.4281~4291 (2020)
- Zhong, Z., "New mitochondrial DNA synthesis enables NLRP3 inflammasome activation", Nature, 560, pp.198~203 (2018)
- Ablasser, A., "Regulation of cGAS-and RLR-mediated immunity to nucleic acids", Nat. Immunol, 21, pp.17~29 (2020)
- Geula, S., "Structure-based analysis of VDAC1 protein : defining oligomer contact sites", J. Biol. Chem, 287, pp.2179~2190 (2012)