Stress granule-localized USP8 potentiates cGAS-mediated type I interferonopathies through deubiquitination of DDX3X
Xuejing Zhang,
Lulu Han,
Jinxiu Hou,
Huiyu Yang,
Haiyan Xu,
Guosheng Li,
Qiang Shu,
Deyu Zhu,
Yi Zheng,
Chengjiang Gao
Affiliations
Xuejing Zhang
Key Laboratory of Infection and Immunity of Shandong Province & Department of Immunology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong 250012, China
Lulu Han
Key Laboratory of Infection and Immunity of Shandong Province & Department of Immunology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong 250012, China
Jinxiu Hou
Key Laboratory of Infection and Immunity of Shandong Province & Department of Immunology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong 250012, China
Huiyu Yang
Key Laboratory of Infection and Immunity of Shandong Province & Department of Immunology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong 250012, China
Haiyan Xu
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong 250012, China
Guosheng Li
Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
Qiang Shu
Department of Rheumatology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
Deyu Zhu
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong 250012, China
Yi Zheng
Key Laboratory of Infection and Immunity of Shandong Province & Department of Immunology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong 250012, China; Corresponding author
Chengjiang Gao
Key Laboratory of Infection and Immunity of Shandong Province & Department of Immunology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong 250012, China; Corresponding author
Summary: Cyclic GMP-AMP synthase (cGAS) undergoes liquid-liquid phase separation (LLPS) to trigger downstream signaling upon double-stranded DNA (dsDNA) stimulation, and the condensed cGAS colocalizes with stress granules (SGs). However, the molecular mechanism underlying the modulation of cGAS activation by SGs remains elusive. In this study, we show that USP8 is localized to SGs upon dsDNA stimulation and potentiates cGAS-stimulator of interferon genes (STING) signaling. A USP8 inhibitor ameliorates pathological inflammation in Trex1−/− mice. Systemic lupus erythematosus (SLE) databases indicate a positive correlation between USP8 expression and SLE. Mechanistic study shows that the SG protein DDX3X promotes cGAS phase separation and activation in a manner dependent on its intrinsic LLPS. USP8 cleaves K27-linked ubiquitin chains from the intrinsically disordered region (IDR) of DDX3X to enhance its condensation. In conclusion, we demonstrate that USP8 catalyzes the deubiquitination of DDX3X to facilitate cGAS condensation and activation and that inhibiting USP8 is a promising strategy for alleviating cGAS-mediated autoimmune diseases.
