[HTML][HTML] SENP7 potentiates cGAS activation by relieving SUMO-mediated inhibition of cytosolic DNA sensing

Y Cui, H Yu, X Zheng, R Peng, Q Wang, Y Zhou… - PLoS …, 2017 - journals.plos.org
Y Cui, H Yu, X Zheng, R Peng, Q Wang, Y Zhou, R Wang, J Wang, B Qu, N Shen, Q Guo…
PLoS pathogens, 2017journals.plos.org
Cyclic GMP-AMP (cGAMP) synthase (cGAS, aka 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 …
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.
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