MYSM1 Represses Innate Immunity and Autoimmunity through Suppressing the cGAS-STING Pathway
Mingfu Tian,
Weiyong Liu,
Qi Zhang,
Yuqing Huang,
Wen Li,
Wenbiao Wang,
Peiyi Zhao,
Shanyu Huang,
Yunting Song,
Muhammad Adnan Shereen,
Mengying Qin,
Yingle Liu,
Kailang Wu,
Jianguo Wu
Affiliations
Mingfu Tian
State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China
Weiyong Liu
State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China
Qi Zhang
State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China
Yuqing Huang
State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China
Wen Li
State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China
Wenbiao Wang
Guangzhou Provincial Key Laboratory of Virology, Institute of Medical Microbiology, Jinan University, Guangzhou 510632, China
Peiyi Zhao
State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China
Shanyu Huang
State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China
Yunting Song
State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China
Muhammad Adnan Shereen
State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China
Mengying Qin
State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China
Yingle Liu
State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China
Kailang Wu
State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China; Corresponding author
Jianguo Wu
State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China; Guangzhou Provincial Key Laboratory of Virology, Institute of Medical Microbiology, Jinan University, Guangzhou 510632, China; Corresponding author
Summary: The immune system is not only required for preventing threats exerted by pathogens but also essential for developing immune tolerance to avoid tissue damage. This study identifies a distinct mechanism by which MYSM1 suppresses innate immunity and autoimmunity. The expression of MYSM1 is induced upon DNA virus infection and by intracellular DNA stimulation. MYSM1 subsequently interacts with STING and cleaves STING K63-linked ubiquitination to suppress cGAS-STING signaling. Notably, Mysm1-deficient mice exhibit a hyper-inflammatory response, acute tissue damage, and high mortality upon virus infection. Moreover, in the PBMCs of patients with systemic lupus erythematosus (SLE), MYSM1 production decreases, while type I interferons and pro-inflammatory cytokine expressions increase. Importantly, MYSM1 treatment represses the production of IFNs and pro-inflammatory cytokines in the PBMCs of SLE patients. Thus, MYSM1 is a critical repressor of innate immunity and autoimmunity and is thus a potential therapeutic agent for infectious, inflammatory, and autoimmune diseases.
