MYSM1 Represses Innate Immunity and Autoimmunity through Suppressing the cGAS-STING Pathway

• Published in: Cell reports (Cambridge) Vol. 33; no. 3; p. 108297
• Main Authors: Tian, Mingfu, Liu, Weiyong, Zhang, Qi, Huang, Yuqing, Li, Wen, Wang, Wenbiao, Zhao, Peiyi, Huang, Shanyu, Song, Yunting, Shereen, Muhammad Adnan, Qin, Mengying, Liu, Yingle, Wu, Kailang, Wu, Jianguo
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.10.2020; Elsevier
• Subjects: adenovirus; ADV; and MPN domains 1 protein; autoimmune disease; autoimmunity; cGAS; cyclic GMP-AMP synthase; herpes simplex virus type 1; HSV-1; innate immunity; Myb-like; MYSM1; pro-inflammatory cytokines; SLE; stimulator of interferon genes; STING; SWIRM; systemic lupus erythematosus; type I interferon; herpes simplex virus type 1; autoimmune disease; SLE; MYSM1; and MPN domains 1 protein; type I interferon; HSV-1; systemic lupus erythematosus; ADV; autoimmunity; innate immunity; cyclic GMP-AMP synthase; pro-inflammatory cytokines; stimulator of interferon genes; adenovirus; cGAS; STING; Myb-like; SWIRM
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.108297

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. [Display omitted] •MYSM1 is induced upon DNA virus infection and stimulation by intracellular DNA•MYSM1 interacts with STING to cleave STING ubiquitination and attenuate the pathway•Mysm1−/− mice induce tissue damage and exhibit early death upon viral infection•MYSM1 acts as a suppressor of autoimmune disease systemic lupus erythematosus Tian et al. show that MYSM1 cleaves STING ubiquitination to suppress the STING pathway. Mysm1-deficient mice exhibit tissue damage and high mortality upon virus infection. MYSM1 treatment represses pro-inflammatory cytokines in PBMCs from patients with systemic lupus erythematosus. Thus, MYSM1 acts a therapeutic agent for infectious and autoimmune diseases.