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

PLoS Pathog. 2017 Jan 17;13(1):e1006156. doi: 10.1371/journal.ppat.1006156. eCollection 2017 Jan.

Abstract

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.

MeSH terms

  • Animals
  • Endopeptidases / immunology*
  • Endopeptidases / metabolism
  • Gene Knockdown Techniques
  • Humans
  • Immunity, Innate / immunology*
  • Immunoblotting
  • Immunoprecipitation
  • Lupus Erythematosus, Systemic / immunology
  • Mice
  • Mice, Inbred C57BL
  • Microscopy, Confocal
  • Nucleotidyltransferases / immunology*
  • Nucleotidyltransferases / metabolism
  • Real-Time Polymerase Chain Reaction
  • Sumoylation

Substances

  • Nucleotidyltransferases
  • cGAS protein, human
  • cGAS protein, mouse
  • Endopeptidases
  • SENP7 protein, human
  • SENP7 protein, mouse

Grants and funding

This work was supported by grants from National Natural Science Foundation of China (31030021, 31300735, 81161120542, 81401331), Ministry of Science and Technology of China (2012CB910200, 2011CB910904, 2014CB541902, 2014CB541906). CW was supported by the 111 Project (No. 111-2-07). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.