SENP7 Potentiates cGAS Activation by Relieving SUMO-Mediated Inhibition of Cytosolic DNA Sensing

PLoS Pathogens

Bo Qu¹  Qiang Guo¹  Nan Shen¹  Jiehua Wang¹  Xing Liu²  Yi Zhou³  Xin Zheng³  Rui Peng³  Chen Wang³  Rui Wang³  Huansha Yu³  Ye Cui³  Qiang Wang³ 

[1] Department of Rheumatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China;Program in Cellular and Molecular Medicine, Boston Children’s Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, United States of America;State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China

关键词: SUMOylation;    Immunoprecipitation;    Small interfering RNAs;    Enzyme-linked immunoassays;    Lysine;    Fluorescence resonance energy transfer;    Interferons;    Transfection;   

DOI  :  10.1371/journal.ppat.1006156

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Cyclic GMP-AMP (cGAMP) synthase (cGAS, a.k.a. MB21D1), a cytosolic DNA sensor, catalyzes formation of the second messenger 2’3’-cGAMP that activates the stimulator of interferon genes (STING) signaling. How the cGAS activity is modulated remains largely unknown. Here, we demonstrate that sentrin/SUMO-specific protease 7 (SENP7) interacted with and potentiated cGAS activation. The small ubiquitin-like modifier (SUMO) was conjugated onto the lysine residues 335, 372 and 382 of cGAS, which suppressed its DNA-binding, oligomerization and nucleotidyl-transferase activities. SENP7 reversed this inhibition via catalyzing the cGAS de-SUMOylation. Consistently, silencing of SENP7 markedly impaired the IRF3-responsive gene expression induced by cGAS-STING axis. SENP7-knockdown mice were more susceptible to herpes simplex virus 1 (HSV-1) infection. SENP7 was significantly up-regulated in patients with SLE. Our study highlights the temporal modulation of the cGAS activity via dynamic SUMOylation, uncovering a novel mechanism for fine-tuning the STING signaling in innate immunity.

【 授权许可】

CC BY