ASC filament formation serves as a signal amplification mechanism for inflammasomes

被引：362

作者：

Dick, Mathias S. ^{[1
]}

Sborgi, Lorenzo ^{[2
]}

Ruhl, Sebastian ^{[1
]}

Hiller, Sebastian ^{[2
]}

Broz, Petr ^{[1
]}

机构：

[1] Univ Basel, Focal Area Infect Biol, Biozentrum, Klingelbergstr 50-70, CH-4056 Basel, Switzerland

[2] Univ Basel, Focal Area Struct Biol, Biozentrum, Klingelbergstr 50-70, CH-4056 Basel, Switzerland

来源：

NATURE COMMUNICATIONS | 2016年 / 7卷

基金：

瑞士国家科学基金会;

关键词：

CASPASE RECRUITMENT DOMAIN; GAMMA-INDUCING FACTOR; NLRP3; INFLAMMASOME; CELL-DEATH; PYRIN DOMAIN; ADAPTER ASC; ACTIVATION; PROTEIN; INTERLEUKIN-1-BETA; APOPTOSIS;

D O I：

10.1038/ncomms11929

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：

A hallmark of inflammasome activation is the ASC speck, a micrometre-sized structure formed by the inflammasome adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD), which consists of a pyrin domain (PYD) and a caspase recruitment domain (CARD). Here we show that assembly of the ASC speck involves oligomerization of ASC(PYD) into filaments and cross-linking of these filaments by ASC(CARD). ASC mutants with a non-functional CARD only assemble filaments but not specks, and moreover disrupt endogenous specks in primary macrophages. Systematic site-directed mutagenesis of ASC(PYD) is used to identify oligomerization-deficient ASC mutants and demonstrate that ASC speck formation is required for efficient processing of IL-1 beta, but dispensable for gasdermin-D cleavage and pyroptosis induction. Our results suggest that the oligomerization of ASC creates a multitude of potential caspase-1 activation sites, thus serving as a signal amplification mechanism for inflammasome-mediated cytokine production.

引用

页数：12

共 66 条

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