CHIP ameliorates nonalcoholic fatty liver disease via promoting K63- and K27-linked STX17 ubiquitination to facilitate autophagosome-lysosome fusion

Hyunjin Rho, Seungyeon Kim, Seung Up Kim, Jeong Won Kim, Sang Hoon Lee, Sang Hoon Park, Freddy E. Escorcia, Joon-Yong Chung and Jaewhan Song ()
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Hyunjin Rho: Institute for Bio-medical Convergence Science and Technology, Yonsei University
Seungyeon Kim: Institute for Bio-medical Convergence Science and Technology, Yonsei University
Seung Up Kim: Yonsei University
Jeong Won Kim: Hallym University College of Medicine
Sang Hoon Lee: Sungkyunkwan University
Sang Hoon Park: Hallym University College of Medicine
Freddy E. Escorcia: National institutes of Health
Joon-Yong Chung: National institutes of Health
Jaewhan Song: Institute for Bio-medical Convergence Science and Technology, Yonsei University

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-53002-0

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