Kindlin-2 inhibits TNF/NF-κB-Caspase 8 pathway in hepatocytes to maintain liver development and function
|Corresponding Author||Bai，Xiaochun; Xiao，Guozhi|
|Joint first author||Zhong，Yiming; Zhou，Liang; Lin，Sixiong; Hou，Xiaoting|
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.
NI Journal Papers
First ; 共同第一 ; Corresponding
National Key Research and Development Program of China[2019YFA0906004] ; National Natural Science Foundation of China["82230081","82250710175","82172375","81991513","81870532"] ; Shenzhen Municipal Science and Technology Innovation Council["JCYJ20220818100617036","JCYJ20180302174246105","ZDSYS20140509142721429"] ; Guangdong Provincial Science and Technology Innovation Council[2017B030301018]
|WOS Research Area|
Life Sciences & Biomedicine - Other Topics
|WOS Accession No|
Web of Science
Cited Times [WOS]:0
|Document Type||Journal Article|
|Department||Department of Biochemistry|
1.Department of Biochemistry,School of Medicine,Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research,Shenzhen Key Laboratory of Cell Microenvironment,Southern University of Science and Technology,Shenzhen,China
2.Guangdong Province Key Laboratory of Pharmaceutical Functional Genes,MOE Key Laboratory of Gene Function and Regulation,State Key Laboratory of Biocontrol,School of Life Sciences,Sun Yat-sen University,Guangzhou,China
3.Guangdong Provincial Key Laboratory of Orthopedics and Traumatology,Department of Spinal Surgery,First Affiliated Hospital of Sun Yat-sen University,Guangzhou,China
4.Department of Biology,Southern University of Science and Technology,Shenzhen,China
5.Research Center for Human Tissues and Organs Degeneration,Shenzhen Institutes of Advanced Technology,Chinese Academy of Sciences,Shenzhen,China
6.Provincial Key Laboratory of Bone and Joint Degeneration Diseases,Department of Cell Biology,School of Basic Medical Sciences,Southern Medical University,Guangzhou,China
|First Author Affilication||Department of Biochemistry; School of Medicine|
|Corresponding Author Affilication||Department of Biochemistry; School of Medicine|
|First Author's First Affilication||Department of Biochemistry; School of Medicine|
Gao，Huanqing,Zhong，Yiming,Zhou，Liang,et al. Kindlin-2 inhibits TNF/NF-κB-Caspase 8 pathway in hepatocytes to maintain liver development and function[J]. eLife,2023,12.
Gao，Huanqing.,Zhong，Yiming.,Zhou，Liang.,Lin，Sixiong.,Hou，Xiaoting.,...&Xiao，Guozhi.(2023).Kindlin-2 inhibits TNF/NF-κB-Caspase 8 pathway in hepatocytes to maintain liver development and function.eLife,12.
Gao，Huanqing,et al."Kindlin-2 inhibits TNF/NF-κB-Caspase 8 pathway in hepatocytes to maintain liver development and function".eLife 12(2023).
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