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

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

Full-length article | 更新时间：2023-08-29

- Hepatocyte nuclear factor 1A suppresses innate immune response by inducing degradation of TBK1 to inhibit steatohepatitis
- Hepatocyte nuclear factor 1A suppresses innate immune response by inducing degradation of TBK1 to inhibit steatohepatitis
- Genes & Diseases 2023年10卷第4期
- 作者机构：
  
  1. Guangdong Province Key Laboratory of Liver Disease Research, The Third Affiliated Hospital, Sun Yat-sen University,Guangdong,Guangzhou,China,510630
  2. Cell-gene Therapy Translational Medicine Research Center, The Third Affiliated Hospital, Sun Yat-sen University,Guangdong,Guangzhou,China,510630
  3. Molecular Cancer Research Center School of Medicine, Sun Yat-sen University,Guangdong,Shenzhen,China,518107
  4. Department of Emergency, The Third Affiliated Hospital, Sun Yat-sen University,Guangdong,Guangzhou,China,510630
  5. Biotherapy Center, The Third Affiliated Hospital, Sun Yat-sen University,Guangdong,Guangzhou,China,510630
- 作者简介：
- 基金信息：
- DOI：10.1016/j.gendis.2022.05.029
  中图分类号：
- 纸质出版日期：2023，
  
  网络出版日期：2023-7-1，
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Jinyong He, Cong Du, Xuyun Peng, 等. Hepatocyte nuclear factor 1A suppresses innate immune response by inducing degradation of TBK1 to inhibit steatohepatitis[J]. Genes & Diseases, 2023,10(4).

Jinyong He, Cong Du, Xuyun Peng, et al. Hepatocyte nuclear factor 1A suppresses innate immune response by inducing degradation of TBK1 to inhibit steatohepatitis[J]. Genes & Diseases, 2023,10(4).
Jinyong He, Cong Du, Xuyun Peng, 等. Hepatocyte nuclear factor 1A suppresses innate immune response by inducing degradation of TBK1 to inhibit steatohepatitis[J]. Genes & Diseases, 2023,10(4). DOI： 10.1016/j.gendis.2022.05.029.

Jinyong He, Cong Du, Xuyun Peng, et al. Hepatocyte nuclear factor 1A suppresses innate immune response by inducing degradation of TBK1 to inhibit steatohepatitis[J]. Genes & Diseases, 2023,10(4). DOI： 10.1016/j.gendis.2022.05.029.

摘要

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.

关键词

Keywords

HNF1AIFN signaling pathwayInnate immunityNAFLDTBK1

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