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Hepatocyte nuclear factor 1A suppresses innate immune response by inducing degradation of TBK1 to inhibit steatohepatitis

查看全文 作　　者：Jinyong [1,2,3,4]He;Cong [1,2,3]Du;Xuyun [1,2,3]Peng;Weilong [5]Hong;Dongbo [1,2,3]Qiu;Xiusheng [1,2,3]Qiu;Xingding [4]Zhang;Yunfei [1,2,3]Qin;Qi [1,2,3]Zhang 高影响力作者 机构地区：[1]Cell-gene Therapy Translational Medicine Research Center,The Third Affiliated Hospital,Sun Yat-sen University,Guangzhou,Guangdong 510630,China;[2]Biotherapy Center,The Third Affiliated Hospital,Sun Yat-sen University,Guangzhou,Guangdong 510630,China;[3]Guangdong Province Key Laboratory of Liver Disease Research,The Third Affiliated Hospital,Sun Yat-sen University,Guangzhou,Guangdong 510630,China;[4]Molecular Cancer Research Center School of Medicine,Sun Yat-sen University,Shenzhen,Guangdong 518107,China;[5]Department of Emergency,The Third Affiliated Hospital,Sun Yat-sen University,Guangzhou,Guangdong 510630,China高影响力机构 出　　处：《Genes & Diseases》索引2023年第10卷第4期,共17页高影响力期刊 基　　金：supported by the National Natural Science Foundation of China(No.81970509,82000620,81870449,81800559);the Fundamental Research Funds for the Central Universities(No.20ykzd03,19ykpy26). 摘　　要：Non-alcoholic steatohepatitis(NASH),a progressive form of non-alcoholic fatty liver disease(NAFLD),is characterised by chronic liver inflammation,which can further prog-ress into complications such as liver cirrhosis and NASH-associated hepatocellular carcinoma(HCC)and therefore has become a growing health problem worldwide.The type I interferon(IFN)signaling pathway plays a pivotal role in chronic inflammation;however,the molecular mechanisms underlying NAFLD/NASH from the perspective of innate immune response has not yet been fully explored.In this study,we elucidated the mechanisms of how innate im-mune response modulates NAFLD/NASH pathogenesis,and demonstrated that hepatocyte nu-clear factor-1alpha(HNF1A)was suppressed and the typeⅠIFN production pathway was activated in liver tissues of patients with NAFLD/NASH.Further experiments suggested that HNF1A negatively regulates the TBK1-IRF3 signaling pathway by promoting autophagic degra-dation of phosphorylated-TBK1,which constrains IFN production,thereby inhibiting the activa-tion of type I IFN signaling.Mechanistically,HNF1A interacts with the phagophore membrane protein LC3 through its LIR-docking sites,and mutations of LIRs(LIR2,LIR3,LIR4,and LIRs)block the HNF1A-LC3 interaction.In addition,HNF1A was identified not only as a novel autop-hagic cargo receptor but also to specifically induce K33-linked ubiquitin chains on TBK1 at Lys670,thereby resulting in autophagic degradation of TBK1.Collectively,our study illustrates the crucial function of the HNF1A-TBK1 signaling axis in NAFLD/NASH pathogenesis via cross-talk between autophagy and innate immunity. 关 键 词：HNF1A IFN signaling pathway Innate immunity NAFLD TBK1
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