Kindlin-2 inhibits TNF/NF-κB-Caspase 8 pathway in hepatocytes to maintain liver development and function

  1. Huanqing Gao
  2. Yiming Zhong
  3. Liang Zhou
  4. Sixiong Lin
  5. Xiaoting Hou
  6. Zhen Ding
  7. Yan Li
  8. Qing Yao
  9. Huiling Cao
  10. Xuenong Zou
  11. Di Chen
  12. Xiaochun Bai  Is a corresponding author
  13. Guozhi Xiao  Is a corresponding author
  1. Southern Taiwan University of Science and Technology, China
  2. Southern University of Science and Technology, China
  3. Sun Yat-sen University, China
  4. Chinese Academy of Sciences, China
  5. Southern Medical University, China

Abstract

Inflammatory liver diseases are a major cause of morbidity and mortality worldwide; however, underlying mechanisms are incompletely understood. Here we show that deleting the focal adhesion protein Kindlin-2 expression in hepatocytes using the Alb-Cre transgenic mice causes a severe inflammation, resulting in premature death. Kindlin-2 loss accelerates hepatocyte apoptosis with subsequent compensatory cell proliferation and accumulation of the collagenous extracellular matrix, leading to massive liver fibrosis and dysfunction. Mechanistically, Kindlin-2 loss abnormally activates the tumor necrosis factor (TNF) pathway. Blocking activation of the TNF signaling pathway by deleting TNF receptor or deletion of Caspase 8 expression in hepatocytes essentially restores liver function and prevents premature death caused by Kindlin-2 loss. Finally, of translational significance, adeno-associated virus mediated overexpression of Kindlin-2 in hepatocytes attenuates the D-galactosamine and lipopolysaccharide-induced liver injury and death in mice. Collectively, we establish that Kindlin-2 acts as a novel intrinsic inhibitor of the TNF pathway to maintain liver homeostasis and may define a useful therapeutic target for liver diseases.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for Figures 1-7 and supplementary figures.

Article and author information

Author details

  1. Huanqing Gao

    Department of Biochemistry, Southern Taiwan University of Science and Technology, Shenzhen, China
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8567-3583
  2. Yiming Zhong

    Department of Biochemistry, Southern University of Science and Technology, Shenzhen, China
    Competing interests
    No competing interests declared.
  3. Liang Zhou

    Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, Sun Yat-sen University, Guangzhou, China
    Competing interests
    No competing interests declared.
  4. Sixiong Lin

    Department of Spinal Surgery, Sun Yat-sen University, Guangzhou, China
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7155-5044
  5. Xiaoting Hou

    Department of Biochemistry, Southern University of Science and Technology, Shenzhen, China
    Competing interests
    No competing interests declared.
  6. Zhen Ding

    Department of Biochemistry, Southern University of Science and Technology, Shenzhen, China
    Competing interests
    No competing interests declared.
  7. Yan Li

    Department of Biology, Southern University of Science and Technology, Shenzhen, China
    Competing interests
    No competing interests declared.
  8. Qing Yao

    Department of Biochemistry, Southern University of Science and Technology, Shenzhen, China
    Competing interests
    No competing interests declared.
  9. Huiling Cao

    Department of Biochemistry, Southern University of Science and Technology, Shenzhen, China
    Competing interests
    No competing interests declared.
  10. Xuenong Zou

    Department of Spinal Surgery, Sun Yat-sen University, Guangzhou, China
    Competing interests
    No competing interests declared.
  11. Di Chen

    Research Center for Computer-aided Drug Discovery, Chinese Academy of Sciences, Shenzhen, China
    Competing interests
    Di Chen, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4258-3457
  12. Xiaochun Bai

    Department of Cell Biology, Southern Medical University, Guangzhou, China
    For correspondence
    baixc15@smu.edu.cn
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9631-4781
  13. Guozhi Xiao

    Department of Biochemistry, Southern University of Science and Technology, Shenzhen, China
    For correspondence
    xiaogz@sustech.edu.cn
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4269-2450

Funding

National Key Research and Development Program of China (2019YFA0906004)

  • Guozhi Xiao

National Natural Science Foundation of China (82230081,82250710175,82172375,81991513 and 81870532)

  • Guozhi Xiao

Shenzhen Municipal Science and Technology Innovation Council (JCYJ20180302174246105)

  • Huanqing Gao

Shenzhen Municipal Science and Technology Innovation Council (JCYJ20220818100617036,ZDSYS20140509142721429)

  • Guozhi Xiao

Guangdong Provincial Science and Technology Innovation Council Grant (2017B030301018)

  • Guozhi Xiao

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal experiments were approved and conducted in the specific pathogen free (SPF) Experimental Animal Center of Southern University of Science and Technology (Approval number: 20200074).

Reviewing Editor

  1. Pramod Mistry, Yale School of Medicine, United States

Version history

  1. Received: July 12, 2022
  2. Preprint posted: July 13, 2022 (view preprint)
  3. Accepted: January 8, 2023
  4. Accepted Manuscript published: January 9, 2023 (version 1)
  5. Version of Record published: January 18, 2023 (version 2)

Copyright

© 2023, Gao et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Huanqing Gao
  2. Yiming Zhong
  3. Liang Zhou
  4. Sixiong Lin
  5. Xiaoting Hou
  6. Zhen Ding
  7. Yan Li
  8. Qing Yao
  9. Huiling Cao
  10. Xuenong Zou
  11. Di Chen
  12. Xiaochun Bai
  13. Guozhi Xiao
(2023)
Kindlin-2 inhibits TNF/NF-κB-Caspase 8 pathway in hepatocytes to maintain liver development and function
eLife 12:e81792.
https://doi.org/10.7554/eLife.81792

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