AIM2 inflammasome is activated by pharmacological disruption of nuclear envelope integrity

被引：119

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

共 82 条

[31] Nelfinavir, a lead HIV protease inhibitor, is a broad-spectrum, anticancer agent that induces endoplasmic reticulum stress, autophagy, and apoptosis in vitro and in vivo [J].

Gills, JoellJ. ;

Lo Piccolo, Jaclyn ;

Tsurutani, Junji ;

Shoemaker, Robert H. ;

Best, Carolyn J. M. ;

Abu-Asab, Mones S. ;

Borojerdi, Jennifer ;

Warfel, Noel A. ;

Gardner, Erin R. ;

Danish, Matthew ;

Hollander, M. Christine ;

Kawabata, Shigeru ;

Tsokos, Maria ;

Figga, William D. ;

Steeg, Patricia S. ;

Dennis, Phillip A. .

CLINICAL CANCER RESEARCH, 2007, 13 (17) :5183-5194

[32] Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson-Gilford progeria syndrome [J].

Goldman, RD ;

Shumaker, DK ;

Erdos, MR ;

Eriksson, M ;

Goldman, AE ;

Gordon, LB ;

Gruenbaum, Y ;

Khuon, S ;

Mendez, M ;

Varga, R ;

Collins, FS .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (24) :8963-8968

[33] Nuclear envelope-related lipodystrophies [J].

Guenantin, A. C. ;

Briand, N. ;

Bidault, G. ;

Afonso, P. ;

Bereziat, V. ;

Vatier, C. ;

Lascols, O. ;

Caron-Debarle, M. ;

Capeau, V. J. ;

Vigouroux, C. .

SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY, 2014, 29 :148-157

[34] Inflammasomes: mechanism of action, role in disease, and therapeutics [J].

Guo, Haitao ;

Callaway, Justin B. ;

Ting, Jenny P-Y .

NATURE MEDICINE, 2015, 21 (07) :677-687

[35] Mitochondria: diversity in the regulation of the NLRP3 inflammasome [J].

Gurung, Prajwal ;

Lukens, John R. ;

Kanneganti, Thirumala-Devi .

TRENDS IN MOLECULAR MEDICINE, 2015, 21 (03) :193-201

[36] Breaching the nuclear, envelope in development and disease [J].

Hatch, Emily ;

Hetzer, Martin .

JOURNAL OF CELL BIOLOGY, 2014, 205 (02) :133-141

[37]

Hennessy M, 2004, ANTIVIR THER, V9, P115

[38] AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC [J].

Hornung, Veit ;

Ablasser, Andrea ;

Charrel-Dennis, Marie ;

Bauernfeind, Franz ;

Horvath, Gabor ;

Caffrey, Daniel. R. ;

Latz, Eicke ;

Fitzgerald, Katherine A. .

NATURE, 2009, 458 (7237) :514-U6

[39] AIM2 Drives Joint Inflammation in a Self-DNA Triggered Model of Chronic Polyarthritis [J].

Jakobs, Christopher ;

Perner, Sven ;

Hornung, Veit .

PLOS ONE, 2015, 10 (06)

[40] Structures of the HIN Domain: DNA Complexes Reveal Ligand Binding and Activation Mechanisms of the AIM2 Inflammasome and IFI16 Receptor [J].

Jin, Tengchuan ;

Perry, Andrew ;

Jiang, Jiansheng ;

Smith, Patrick ;

Curry, James A. ;

Unterholzner, Leonie ;

Jiang, Zhaozhao ;

Horvath, Gabor ;

Rathinam, Vijay A. ;

Johnstone, Ricky W. ;

Hornung, Veit ;

Latz, Eicke ;

Bowie, Andrew G. ;

Fitzgerald, Katherine A. ;

Xiao, T. Sam .

IMMUNITY, 2012, 36 (04) :561-571

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