Abstract
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.
Highlights
Innate immunity initiates and regulates adaptive immune responses, including both normal immunity and autoimmunity
STING does not detect DNA directly but uses cyclic guanosine monophosphate (GMP)-AMP synthase as a DNA sensor (Ablasser et al, 2013; Diner et al, 2013; Sun et al, 2013; Wu et al, 2013). cGAS binds to foreign DNA in the cytoplasm and synthesizes cGAMP, which acts as a second messenger of STING; cGAMP activates the signaling cascade, inducing antiviral and inflammatory responses (Cai et al, 2014)
The results indicated that Mysm1 mRNA was induced by herpes simplex virus type 1 (HSV-1) (Figure 1A) and poly(dA:dT) (Figure 1B) in human acute monocytic leukemia (THP-1) cell-derived macrophages
Summary
Innate immunity initiates and regulates adaptive immune responses, including both normal immunity and autoimmunity. Innate immunity has an important function in the initiation, progression, and subsistence of autoimmune diseases, which develop when regulatory mechanisms of self-tolerance become impaired or dysregulated (Zouali and La Cava, 2019; Toubi and Vadasz, 2019). CGAS binds to foreign DNA in the cytoplasm and synthesizes cGAMP, which acts as a second messenger of STING; cGAMP activates the signaling cascade, inducing antiviral and inflammatory responses (Cai et al, 2014). STING plays a crucial role in innate immune responses to herpes simplex virus type 1 (HSV-1) and Listeria monocytogenes in STING-deficient cells and upon recognition of intracellular DNA in STING-knockout mice (Ishikawa and Barber, 2008; Ishikawa et al, 2009). The dysregulation of STING produces excessive amounts of inflammatory mediators, resulting in the development of inflammatory or immune diseases (Barber, 2011). The cGAS/STING signaling pathway plays a critical pathogenic role in systemic lupus erythematosus (SLE) (Kato et al, 2018; Wang et al, 2018)
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