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

• DOI: 10.1371/journal.ppat.1006156
• Publication Date: 2017-01-17T14:24:14Z
• Authors: Ye Cui; Huansha Yu; Xin Zheng; Rui Peng; Qiang Wang; Yi Zhou; Rui Wang; Jiehua Wang; Bo Qu; Nan Shen; Qiang Guo; Xing Liu; Chen Wang
• Keywords: 0301 basic medicine; Physiology; Biochemistry; Fluorophotometry; Mice; Spectrum Analysis Techniques; Immune Physiology; Medicine and Health Sciences; Fluorescence Resonance Energy Transfer; Lupus Erythematosus, Systemic; Small interfering RNAs; Amino Acids; Enzyme-Linked Immunoassays; Biology (General); Immune System Proteins; Microscopy, Confocal; Organic Compounds; Nucleotidyltransferases; SUMOylation; Precipitation Techniques; 3. Good health; Nucleic acids; Chemistry; Spectrophotometry; Gene Knockdown Techniques; Physical Sciences; Post-translational modification; Basic Amino Acids; Research Article; 570; QH301-705.5; Immunology; Immunoblotting; 610; Real-Time Polymerase Chain Reaction; Antibodies; 03 medical and health sciences; Endopeptidases; Genetics; Animals; Humans; Immunoprecipitation; Non-coding RNA; Immunoassays; Biology and life sciences; Lysine; Organic Chemistry; Chemical Compounds; Proteins; Sumoylation; RC581-607; Immunity, Innate; Gene regulation; Mice, Inbred C57BL; Immunologic Techniques; RNA; Gene expression; Interferons; Immunologic diseases. Allergy

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.