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

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

doi:10.1016/j.gendis.2022.05.029

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

Genes Dis. 2022 Jun 7;10(4):1596-1612. doi: 10.1016/j.gendis.2022.05.029. eCollection 2023 Jul.

Authors

Jinyong He^{1

2

3

4}, Cong Du^{1

2

3}, Xuyun Peng^{1

2

3}, Weilong Hong⁵, Dongbo Qiu^{1

2

3}, Xiusheng Qiu^{1

2

3}, Xingding Zhang⁴, Yunfei Qin^{1

2

3}, Qi Zhang^{1

2

3}

Affiliations

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.

Abstract

Non-alcoholic steatohepatitis (NASH), a progressive form of non-alcoholic fatty liver disease (NAFLD), is characterised by chronic liver inflammation, which can further progress 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 immune response modulates NAFLD/NASH pathogenesis, and demonstrated that hepatocyte nuclear factor-1alpha (HNF1A) was suppressed and the type I IFN 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 degradation of phosphorylated-TBK1, which constrains IFN production, thereby inhibiting the activation 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 autophagic 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.

Keywords: HNF1A; IFN signaling pathway; Innate immunity; NAFLD; TBK1.