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

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.

Species-Specific Deamidation of cGAS by Herpes Simplex Virus UL37 Protein Facilitates Viral Replication

“…In this study, we show that deamidation of cGAS by UL37 specifically ablated the cGAMP-synthesizing activity of cGAS. Previous studies have shown that cGAS is subjected to diverse post-translational modifications, including sumoylation, glutamylation and phosphorylation (Cui et al, 2017; Hu et al, 2016; Seo et al, 2015; Xia et al, 2016), and direct antagonism by an array of microbial proteins (Aguirre et al, 2017; Wu et al, 2015; Zhang et al, 2016a). How deamidation, of RIG-I and cGAS, cross-talks with these regulatory mechanisms remain unclear and these potential cross-talks, if exist, will connect protein deamidation to other well-established signaling cascades and expand the functional repertoire of protein deamidation in high eukaryotes.…”

“…Surprisingly, our understanding in cGAS regulation is in its infancy at best. Previous work has shown that post-translational modifications, including phosphorylation, sumolyation and glutamylation, modulate cGAS enzyme activity directly or indirectly (Cui et al, 2017; Hu et al, 2016; Seo et al, 2015; Xia et al, 2016). Investigating the evasion mechanism of herpes simplex virus 1 (HSV-1) conveyed by the UL37 protein deamidase, we discovered that human and mouse cGAS proteins, but not nonhuman primate cGAS, are targeted for deamidation by UL37.…”

SUMO-specific proteases and isopeptidases of the SENP family at a glance

“…This pathway senses cytosolic DNA in cells infected by certain viruses or bacteria, and triggers the expression of inflammatory genes through interferon 3 (IRF3) (Maringer and Fernandez-Sesma, 2014). SENP7 has been proposed to potentiate cGAS-STING activation by reversing an inhibitory SUMOylation of cGAS (Cui et al, 2017). Consistent with this idea, mice lacking SENP7 are more susceptible to herpes simplex virus 1 (HSV-1) infection and exhibit an impaired gene expression pattern upon induction of the cGAS-STING axis (Cui et al, 2017).…”

Regulation of cGAS‐Mediated Immune Responses and Immunotherapy

“…The conjunction of small ubiquitin‐like modifier (SUMO) in cGAS on K335, K372, and K382 sites suppresses DNA binding, nucleotidyltransferase activity, and oligomerization. Conversely, sentrin/SUMO‐specific protease 7 (SENP7) reverses this inhibitory effect by catalyzing the cGAS deSUMOylation during HSV1 infection 55…”