한빛사논문
Hyunjin Rho 1, Seungyeon Kim 1, Seung Up Kim 2, Jeong Won Kim 3, Sang Hoon Lee 4,5, Sang Hoon Park 6, Freddy E. Escorcia 7, Joon-Yong Chung 7 & Jaewhan Song 1,*
1Department of Biochemistry, College of Life Science and Technology, Yonsei University, Seoul, Republic of Korea.
2Department of Internal Medicine, College of Medicine, Yonsei University, Seoul, Republic of Korea.
3Department of Pathology, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Republic of Korea.
4Department of Digital Health, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Republic of Korea.
5GENINUS Inc, Seoul, Republic of Korea.
6Department of Internal Medicine, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Republic of Korea.
7Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, National institutes of Health, Bethesda, MD, USA
*Corresponding author: correspondence to Jaewhan Song
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.
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