A bacteria-derived tetramerized protein ameliorates nonalcoholic steatohepatitis in mice via binding and relocating acetyl-coA carboxylase
Yan Lin,
Mingkun Yang,
Li Huang,
Fan Yang,
Jiachen Fan,
Yulong Qiang,
Yuting Chang,
Wenjie Zhou,
Leilei Yan,
Jie Xiong,
Jie Ping,
Shizhen Chen,
Dong Men,
Feng Li
Affiliations
Yan Lin
Department of Medical Genetics, TaiKang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan 430071, China
Mingkun Yang
State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
Li Huang
Research Center for Medicine and Structural Biology, TaiKang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan 430071, China
Fan Yang
Department of Medical Genetics, TaiKang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan 430071, China
Jiachen Fan
Department of Medical Genetics, TaiKang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan 430071, China
Yulong Qiang
Department of Medical Genetics, TaiKang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan 430071, China
Yuting Chang
Department of Medical Genetics, TaiKang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan 430071, China
Wenjie Zhou
Department of Medical Genetics, TaiKang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan 430071, China
Leilei Yan
Department of Medical Genetics, TaiKang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan 430071, China
Jie Xiong
Department of Immunology, TaiKang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan 430071, China
Jie Ping
Department of Pharmacology, TaiKang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan 430071, China
Shizhen Chen
State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Center for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences, Wuhan 430071, China
Dong Men
Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou 510005, Guangdong Province, China; Corresponding author
Feng Li
Department of Medical Genetics, TaiKang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan 430071, China; Hubei Provincial Key Laboratory of Allergy and Immunology, Wuhan 430071, China; Corresponding author
Summary: Increased de novo lipogenesis (DNL) is a major feature of nonalcoholic steatohepatitis (NASH). None of the drugs targeting the catalytic activity of acetyl-CoA carboxylase (ACC), the rate-limiting enzyme in the DNL process, have been approved by the FDA. Whether cytosolic ACC1 can be regulated spatially remains to be explored. Herein, we find that streptavidin (SA), which is a bacterium-derived tetrameric protein, forms cytosolic condensates and efficiently induces a spatial re-localization of ACC1 in liver cells, concomitant with inhibited lipid accumulation. Both SA tetrameric structure and multivalent protein interaction are required for condensate formation. Interestingly, the condensates are further characterized as gel-like membraneless organelle (SAGMO) and significantly restrict the cytosolic dispersion of ACC1 and fatty acid synthase. Notably, AAV-mediated delivery of SA partially blocks mouse liver DNL and ameliorates NASH without eliciting hypertriglyceridemia. In summary, our study shows that insulating lipogenesis-related proteins by SAGMO might be effective for NASH treatment.
