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Full Length Article | Open Access

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

Jinyong Hea,b,c,d,1, Cong Dua,b,c,1, Xuyun Penga,b,c, Weilong Honge, Dongbo Qiua,b,c, Xiusheng Qiua,b,c, Xingding Zhangd( ), Yunfei Qina,b,c( ), Qi Zhanga,b,c( )
Cell-gene Therapy Translational Medicine Research Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, China
Biotherapy Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, China
Guangdong Province Key Laboratory of Liver Disease Research, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, China
Molecular Cancer Research Center School of Medicine, Sun Yat-sen University, Shenzhen, Guangdong 518107, China
Department of Emergency, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, China

Peer review under responsibility of Chongqing Medical University.

1 These authors contributed equally to this work.

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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

HNF1AIFN signaling pathwayInnate immunityNAFLDTBK1

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Genes & Diseases
Volume 10 Issue 4,
July 2023
Pages 1596-1612
DOI: 10.1016/j.gendis.2022.05.029
Cite this article:
He J, Du C, Peng X, et al. Hepatocyte nuclear factor 1A suppresses innate immune response by inducing degradation of TBK1 to inhibit steatohepatitis. Genes & Diseases, 2023, 10(4): 1596-1612. https://doi.org/10.1016/j.gendis.2022.05.029

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Received: 22 December 2021
Revised: 05 May 2022
Accepted: 26 May 2022
Published: 07 June 2022
© 2022 The Authors.

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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