SUMO-mediated regulation of NLRP3 modulates inflammasome activity

被引：188

作者：

Barry, Rachael ^{[1
,2
]}

John, Sidonie Wicky ^{[1
]}

Liccardi, Gianmaria ^{[1
]}

Tenev, Tencho ^{[1
]}

Jaco, Isabel ^{[1
]}

Chen, Chih-Hong ^{[3
]}

Choi, Justin ^{[3
]}

Kasperkiewicz, Paulina ^{[4
]}

Fernandes-Alnemri, Teresa ^{[5
]}

Alnemri, Emad ^{[5
]}

Drag, Marcin ^{[4
]}

Chen, Yuan ^{[3
]}

Meier, Pascal ^{[1
]}

机构：

[1] Breast Canc Now Toby Robins Res Ctr, Inst Canc Res, Chester Beatty Labs, Mary Jean Mitchell Green Bldg,237 Fulham Rd, London SW3 6JB, England

[2] Imperial Coll London, Dept Life Sci, MRC Ctr Mol Bacteriol & Infect, London SW7 2AZ, England

[3] City Hope Natl Med Ctr, Beckman Res Inst, Dept Mol Med, Duarte, CA 91010 USA

[4] Wroclaw Univ Technol, Dept Chem, Div Bioorgan Chem, Wyb Wyspianskiego 27, PL-50370 Wroclaw, Poland

[5] Thomas Jefferson Univ, Kimmel Canc Ctr, Dept Biochem & Mol Biol, Philadelphia, PA 19107 USA

来源：

NATURE COMMUNICATIONS | 2018年 / 9卷

基金：

英国生物技术与生命科学研究理事会;

关键词：

NF-KAPPA-B; PROTEIN MODIFICATION; SUMOYLATION SITES; IN-SITU; ACTIVATION; CRYOPYRIN; DISEASE; HEALTH; DEUBIQUITINATION; PHOSPHORYLATION;

D O I：

10.1038/s41467-018-05321-2

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

The NLRP3 inflammasome responds to infection and tissue damage, and rapidly escalates the intensity of inflammation by activating interleukin (IL)-1 beta, IL-18 and cell death by pyroptosis. How the NLRP3 inflammasome is negatively regulated is poorly understood. Here we show that NLRP3 inflammasome activation is suppressed by sumoylation. NLRP3 is sumoylated by the SUMO E3-ligase MAPL, and stimulation-dependent NLRP3 desumoylation by the SUMO-specific proteases SENP6 and SENP7 promotes NLRP3 activation. Defective NLRP3 sumoylation, either by NLRP3 mutation of SUMO acceptor lysines or depletion of MAPL, results in enhanced caspase-1 activation and IL-1 beta release. Conversely, depletion of SENP7 suppresses NLRP3-dependent ASC oligomerisation, caspase-1 activation and IL-1 beta release. These data indicate that sumoylation of NLRP3 restrains inflammasome activation, and identify SUMO proteases as potential drug targets for the treatment of inflammatory diseases.

引用

页数：14

共 61 条

[1]

Heterologous SUMO-2/3-Ubiquitin Chains Optimize IκBα Degradation and NF-κB Activity [J].