Date Published: January 17, 2017
Publisher: Public Library of Science
Author(s): 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, Pinghui Feng.
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.
Cytosolic aberrant DNA is generally sensed as a danger signal to alert the host about the presence of invading microbes, which triggers the immediate immune responses to control microbial invasion and induces the subsequent adaptive immunity effective for ultimately eradicating infection. Elucidating the cytosolic-DNA-triggered signaling pathway and the relevant regulatory mechanisms represents a fast evolving field to understand the corresponding innate immunity.
Recent breakthroughs have uncovered the essential function of the cGAS-STING axis in monitoring cytosolic microbial DNAs, which triggers the expression of type-I interferons (IFNs) and pro-inflammatory cytokines. Given that cGAS senses DNAs in a sequence-independent manner, any aberrant activation of the cGAS by cytosolic DNAs contributes to the pathogenesis of chronic inflammation and autoimmune diseases. Hypothetically, the strength and duration of the cGAS-STING signaling is subjected to multiple layers of stringent modulations, so that the balance of the immune homeostasis could be appropriately maintained. It remains intriguing how cGAS is spatially and temporally modulated in immunity.