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

被引：127

作者：

Cui, Ye ^{[1
]}

Yu, Huansha ^{[1
]}

Zheng, Xin ^{[1
]}

Peng, Rui ^{[1
]}

Wang, Qiang ^{[1
]}

Zhou, Yi ^{[1
]}

Wang, Rui ^{[1
]}

Wang, Jiehua ^{[2
]}

Qu, Bo ^{[2
]}

Shen, Nan ^{[2
]}

Guo, Qiang ^{[2
]}

Liu, Xing ^{[3
,4
]}

Wang, Chen ^{[1
,5
,6
]}

机构：

[1] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, State Key Lab Cell Biol,CAS Ctr Excellence Mol Ce, Shanghai, Peoples R China

[2] Shanghai Jiao Tong Univ, Sch Med, Renji Hosp, Dept Rheumatol, Shanghai, Peoples R China

[3] Harvard Med Sch, Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA

[4] Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA

[5] China Pharmaceut Univ, State Key Lab Nat Med, Nanjing, Jiangsu, Peoples R China

[6] China Pharmaceut Univ, Sch Life Sci & Technol, Nanjing, Jiangsu, Peoples R China

来源：

PLOS PATHOGENS | 2017年 / 13卷 / 01期

基金：

中国国家自然科学基金;

关键词：

CYCLIC GMP-AMP; SYSTEMIC-LUPUS-ERYTHEMATOSUS; MYCOBACTERIUM-TUBERCULOSIS; INNATE IMMUNITY; SENSOR CGAS; IMMUNOGENIC TUMORS; SELF-DNA; SYNTHASE; DISEASE; VIRUS;

D O I：

10.1371/journal.ppat.1006156

中图分类号：

Q93 [微生物学];

学科分类号：

071005 [微生物学];

摘要：

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.

引用

页数：24

共 56 条

[1]

Cell intrinsic immunity spreads to bystander cells via the intercellular transfer of cGAMP [J].