SENP3 protects hepatocyte from pyroptosis during acute liver injury through deSUMOylation of HNRNPL
Xinyuan Xiong,
Yang Zhi,
Nan Yang,
Wenzhen Zhao,
Shu Wang,
Huiqin Zhu,
Jieting Tang,
Jing Yi,
Xuxu Sun,
Jie Yang
Affiliations
Xinyuan Xiong
Department of Biochemistry and Molecular Cell Biology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Yang Zhi
Division of Gastroenterology and Hepatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, NHC Key Laboratory of Digestive Diseases, Shanghai Research Center of Fatty Liver Disease, Shanghai, China
Nan Yang
Department of Biochemistry and Molecular Cell Biology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Wenzhen Zhao
Department of Biochemistry and Molecular Cell Biology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Histology and Embryology, School of Basic Medical Science, Dali University, Dali, China
Shu Wang
Department of Biochemistry and Molecular Cell Biology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Huiqin Zhu
Department of Biochemistry and Molecular Cell Biology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Jieting Tang
Division of Gastroenterology and Hepatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, NHC Key Laboratory of Digestive Diseases, Shanghai Research Center of Fatty Liver Disease, Shanghai, China
Jing Yi
Department of Biochemistry and Molecular Cell Biology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Xuxu Sun
Department of Biochemistry and Molecular Cell Biology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Corresponding author
Jie Yang
Department of Biochemistry and Molecular Cell Biology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Corresponding author
Summary: Protein SUMOylation is crucial in both physiological and pathological contexts, but its role in acute liver injury (ALI) is poorly understood. We found that SENP3, a SUMO2/3 protease, rapidly accumulates in hepatocytes around the pericentral vein zone within 2 h of carbon tetrachloride (CCl4)-induced liver injury in mice. Knockout of SENP3 in hepatocytes worsens liver damage and promotes pyroptosis. Mechanistically, SENP3 interacts with the RNA-binding protein HNRNPL, facilitating its deSUMOylation and proteasomal degradation. This reduction of HNRNPL decreases nuclear paraspeckle assembly transcript 1 (Neat1) levels, impairing its ability to activate caspase-1 and induce pyroptosis. Moreover, in patients with drug-induced ALI, the levels of both SENP3 and HNRNPL are strongly correlated with pyroptosis. In conclusion, the SENP3-HNRNPL-Neat1 axis functions as a rapid stress sensor to mitigate excessive pyroptosis during ALI, making SENP3 and HNRNPL promising therapeutic targets.
