1. CHIP ameliorates nonalcoholic fatty liver disease via promoting K63- and K27-linked STX17 ubiquitination to facilitate autophagosome-lysosome fusion.
- Author
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Rho H, Kim S, Kim SU, Kim JW, Lee SH, Park SH, Escorcia FE, Chung JY, and Song J
- Subjects
- Animals, Mice, Humans, Diet, High-Fat adverse effects, Male, Qa-SNARE Proteins metabolism, Qa-SNARE Proteins genetics, Hepatocytes metabolism, Disease Models, Animal, Liver metabolism, Liver pathology, Mice, Inbred C57BL, R-SNARE Proteins metabolism, R-SNARE Proteins genetics, Membrane Fusion, Autophagy, Transcription Factor TFIIH, Lysosomes metabolism, Non-alcoholic Fatty Liver Disease metabolism, Non-alcoholic Fatty Liver Disease pathology, Non-alcoholic Fatty Liver Disease genetics, Ubiquitination, Autophagosomes metabolism, Mice, Knockout, Ubiquitin-Protein Ligases metabolism, Ubiquitin-Protein Ligases genetics
- Abstract
The fusion of autophagosomes and lysosomes is essential for the prevention of nonalcoholic fatty liver disease (NAFLD). Here, we generate a hepatocyte-specific CHIP knockout (H-KO) mouse model that develops NAFLD more rapidly in response to a high-fat diet (HFD) or high-fat, high-fructose diet (HFHFD). The accumulation of P62 and LC3 in the livers of H-KO mice and CHIP-depleted cells indicates the inhibition of autophagosome-lysosome fusion. AAV8-mediated overexpression of CHIP in the murine liver slows the progression of NAFLD induced by HFD or HFHFD feeding. Mechanistically, CHIP induced K63- and K27-linked polyubiquitination at the lysine 198 residue of STX17, resulting in increased STX17-SNAP29-VAMP8 complex formation. The STX17 K198R mutant was not ubiquitinated by CHIP; it interfered with its interaction with VAMP8, rendering STX17 incapable of inhibiting steatosis development in mice. These results indicate that a signaling regulatory mechanism involving CHIP-mediated non-degradative ubiquitination of STX17 is necessary for autophagosome-lysosome fusion., (© 2024. The Author(s).)
- Published
- 2024
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