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
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
Liang Zhou
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
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; Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Department of Spinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
Xiaoting Hou
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
Zhen Ding
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
Yan Li
Department of Biology, Southern University of Science and Technology, Shenzhen, China
Qing Yao
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
Huiling Cao
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
Xuenong Zou
Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Department of Spinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
Provincial Key Laboratory of Bone and Joint Degeneration Diseases, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
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
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.
