L-lactic acid enhances type I interferon immune response and inhibits virus infection by promoting IRF9 L-lactylation
Abstract
Lysine lactylation is a crucial posttranslational modification (PTM) that regulates protein function. Here, this study revealed that L-lactic acid promotes host immune response and inhibits viral infection by inducing Interferon Regulatory Factor 9 (IRF9) L-lactylation. We first found L-lactylation modification (L-Kla) of IRF9 mediated by AARS1. Further studies demonstrated that IRF9 L-lactylation potentiates type I interferon (IFN-I) signaling by promoting IRF9–STAT2 interaction, thereby boosting antiviral immune response. Intriguingly, L-lactic acid exhibits dual effects on viral infection: L-lactic acid exhibits antiviral effects at physiological and moderately elevated levels but proviral effects at high levels. Furthermore, we found that the viruses can achieve immune evasion by promoting SIRT1-mediated delactylation of IRF9. Interestingly, we uncovered that metformin promotes IRF9 L-lactylation by both accumulating lactic acid and disrupting virus-induced IRF9–SIRT1 interaction. These findings renew the understanding of the roles of lactic acid in antiviral immune response and determine metformin’s immunomodulatory effects on antiviral immunity through regulating IRF9 L-lactylation.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (14)
Ying Miao
Hefei National Research Center for Physical Sciences at the Microscale, Chinese Academy of Sciences Key Laboratory of Brain Function and Disease, Biomedical Sciences and Health Laboratory of Anhui Province, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China
Qun Cui
Institutes of Biology and Medical Sciences, Jiangsu Key Laboratory of Infection and Immunity, Soochow University
Tingting Zhang
State Key Laboratory of Bioinspired Interfacial Materials Science, Innovation Center for Chemical Science, College of Chemistry Chemical Engineering and Materials Science
Renxia Zhang
Institutes of Biology and Medical Sciences, Jiangsu Key Laboratory of Infection and Immunity, Soochow University
Qian Zhao
Zhejiang University , , ,
Haiyan Zhou
Department of Chemistry, State Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong SAR 999077, P. R. China
Yibo Zuo
Department of Laboratory Medicine, Institute of Laboratory Medicine, Translational Clinical Immunology Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China
Qin Wang
Yuerong Zhang
Department of Laboratory Medicine, Institute of Laboratory Medicine, Translational Clinical Immunology Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China
Zhijin Zheng
Institutes of Biology and Medical Sciences, Jiangsu Key Laboratory of Infection and Immunity, Soochow University
Wei He
Chunyan Liu
Laboratory of Advanced Materials, College of Smart Materials and Future Energy (iCOME)
Yukang Yuan
Department of Laboratory Medicine, Institute of Laboratory Medicine, Translational Clinical Immunology Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China
Hui Zheng
Department of Clinical Laboratory, Centre for Leading Medicine and Advanced Technologies of Institute of Health and Medicine, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China