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

作     者：Jinyong He Cong Du Xuyun Peng Weilong Hong Dongbo Qiu Xiusheng Qiu Xingding Zhang Yunfei Qin Qi Zhang Jinyong He;Cong Du;Xuyun Peng;Weilong Hong;Dongbo Qiu;Xiusheng Qiu;Xingding Zhang;Yunfei Qin;Qi Zhang

作者机构：Cell-gene Therapy Translational Medicine Research CenterThe Third Affiliated HospitalSun Yat-sen UniversityGuangzhouGuangdong 510630China Biotherapy CenterThe Third Affiliated HospitalSun Yat-sen UniversityGuangzhouGuangdong 510630China Guangdong Province Key Laboratory of Liver Disease ResearchThe Third Affiliated HospitalSun Yat-sen UniversityGuangzhouGuangdong 510630China Molecular Cancer Research Center School of MedicineSun Yat-sen UniversityShenzhenGuangdong 518107China Department of EmergencyThe Third Affiliated HospitalSun Yat-sen UniversityGuangzhouGuangdong 510630China 

出 版 物：《Genes & Diseases》 (基因与疾病（英文）)

年 卷 期：2023年第10卷第4期

页      面：1596-1612页

核心收录：

学科分类：1002[医学-临床医学] 100201[医学-内科学(含：心血管病、血液病、呼吸系病、消化系病、内分泌与代谢病、肾病、风湿病、传染病)] 10[医学] 

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) 

主　　题：HNF1A IFN signaling pathway Innate immunity NAFLD TBK1 

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 *** 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 *** 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/*** 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 ***,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 *** 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 ***,our study illustrates the crucial function of the HNF1A-TBK1 signaling axis in NAFLD/NASH pathogenesis via cross-talk between autophagy and innate immunity.