AIM2 inflammasome is activated by pharmacological disruption of nuclear envelope integrity

被引：115

作者：

Di Micco, Antonia ^{[1
]}

Frera, Gianluca ^{[1
]}

Lugrin, Jerome ^{[1
]}

Jamilloux, Yvan ^{[1
,2
]}

Hsu, Erh-Ting ^{[3
]}

Tardivel, Aubry ^{[1
]}

De Gassart, Aude ^{[1
]}

Zaffalon, Lea ^{[1
]}

Bujisic, Bojan ^{[1
]}

Siegert, Stefanie ^{[4
]}

Quadroni, Manfredo ^{[5
]}

Broz, Petr ^{[6
]}

Henry, Thomas ^{[2
]}

Hrycyna, Christine A. ^{[3
,7
]}

Martinon, Fabio ^{[1
]}

机构：

[1] Univ Lausanne, Dept Biochem, CH-1066 Epalinges, Switzerland

[2] Ctr Infectiol Res, INSERM, U1111, F-69007 Lyon, France

[3] Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA

[4] Univ Lausanne, Ludwig Ctr Canc Res, Flow Cytometry Facil, CH-1066 Epalinges, Switzerland

[5] Univ Lausanne, Ctr Integrat Genom, Prot Anal Facil, CH-1015 Lausanne, Switzerland

[6] Univ Basel, Biozentrum, Focal Area Infect Biol, CH-4056 Basel, Switzerland

[7] Purdue Univ, Purdue Ctr Canc Res, W Lafayette, IN 47907 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2016年 / 113卷 / 32期

基金：

欧洲研究理事会;

关键词：

inflammasome; nuclear envelope stress; DNA sensors; zmpste24; Nelfinavir; THIOREDOXIN-INTERACTING PROTEIN; ENDOPLASMIC-RETICULUM STRESS; P-GLYCOPROTEIN EXPRESSION; HIV-INFECTED PATIENTS; NLRP3; INFLAMMASOME; CELL-DEATH; ER STRESS; NALP3; CYTOPLASMIC DNA; INNATE IMMUNITY;

D O I：

10.1073/pnas.1602419113

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：

07 ; 0710 ; 09 ;

摘要：

Inflammasomes are critical sensors that convey cellular stress and pathogen presence to the immune system by activating inflammatory caspases and cytokines such as IL-1 beta. The nature of endogenous stress signals that activate inflammasomes remains unclear. Here we show that an inhibitor of the HIV aspartyl protease, Nelfinavir, triggers inflammasome formation and elicits an IL-1R-dependent inflammation in mice. We found that Nelfinavir impaired the maturation of lamin A, a structural component of the nuclear envelope, thereby promoting the release of DNA in the cytosol. Moreover, deficiency of the cytosolic DNA-sensor AIM2 impaired Nelfinavir-mediated inflammasome activation. These findings identify a pharmacologic activator of inflammasome and demonstrate the role of AIM2 in detecting endogenous DNA release upon perturbation of nuclear envelope integrity.

引用

页码：E4671 / E4680

页数：10

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