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

[61] Thioredoxin-Interacting Protein Mediates ER Stress-Induced β Cell Death through Initiation of the Inflammasome [J].

Oslowski, Christine M. ;

Hara, Takashi ;

O'Sullivan-Murphy, Bryan ;

Kanekura, Kohsuke ;

Lu, Simin ;

Hara, Mariko ;

Ishigaki, Shinsuke ;

Zhu, Lihua J. ;

Hayashi, Emiko ;

Hui, Simon T. ;

Greiner, Dale ;

Kaufman, Randal J. ;

Bortell, Rita ;

Urano, Fumihiko .

CELL METABOLISM, 2012, 16 (02) :265-273

[62] Lamins at the crossroads of mechanosignaling [J].

Osmanagic-Myers, Selma ;

Dechat, Thomas ;

Foisner, Roland .

GENES & DEVELOPMENT, 2015, 29 (03) :225-237

[63] Nuclear lamina defects cause ATM-dependent NF-κB activation and link accelerated aging to a systemic inflammatory response [J].

Osorio, Fernando G. ;

Barcena, Clea ;

Soria-Valles, Clara ;

Ramsay, Andrew J. ;

de Carlos, Felix ;

Cobo, Juan ;

Fueyo, Antonio ;

Freije, Jose M. P. ;

Lopez-Otin, Carlos .

GENES & DEVELOPMENT, 2012, 26 (20) :2311-2324

[64] Immune Sensing of DNA [J].

Paludan, Soren R. ;

Bowie, Andrew G. .

IMMUNITY, 2013, 38 (05) :870-880

[65] HIV Protease Inhibitors Do Not Cause the Accumulation of Prelamin A in PBMCs from Patients Receiving First Line Therapy: The ANRS EP45 "Aging" Study [J].

Perrin, Sophie ;

Cremer, Jonathan ;

Faucher, Olivia ;

Reynes, Jacques ;

Dellamonica, Pierre ;

Micallef, Joelle ;

Solas, Caroline ;

Lacarelle, Bruno ;

Stretti, Charlotte ;

Kaspi, Elise ;

Robaglia-Schlupp, Andree ;

Tamalet, Corine Nicolino-Brunet Catherine ;

Levy, Nicolas ;

Poizot-Martin, Isabelle ;

Cau, Pierre ;

Roll, Patrice .

PLOS ONE, 2012, 7 (12)

[66] Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration [J].

Petrilli, V. ;

Papin, S. ;

Dostert, C. ;

Mayor, A. ;

Martinon, F. ;

Tschopp, J. .

CELL DEATH AND DIFFERENTIATION, 2007, 14 (09) :1583-1589

[67] The nuclear lamina and its proposed roles in tumorigenesis: Projection on the hematologic malignancies and future targeted therapy [J].

Prokocimer, Miron ;

Margalit, Ayelet ;

Gruenbaum, Yosef .

JOURNAL OF STRUCTURAL BIOLOGY, 2006, 155 (02) :351-360

[68] ESCRT III repairs nuclear envelope ruptures during cell migration to limit DNA damage and cell death [J].

Raab, M. ;

Gentili, M. ;

de Belly, H. ;

Thiam, H. R. ;

Vargas, P. ;

Jimenez, A. J. ;

Lautenschlaeger, F. ;

Voituriez, Raphael ;

Lennon-Dumenil, A. M. ;

Manel, N. ;

Piel, M. .

SCIENCE, 2016, 352 (6283) :359-362

[69] The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses [J].

Rathinam, Vijay A. K. ;

Jiang, Zhaozhao ;

Waggoner, Stephen N. ;

Sharma, Shruti ;

Cole, Leah E. ;

Waggoner, Lisa ;

Vanaja, Sivapriya Kailasan ;

Monks, Brian G. ;

Ganesan, Sandhya ;

Latz, Eicke ;

Hornung, Veit ;

Vogel, Stefanie N. ;

Szomolanyi-Tsuda, Eva ;

Fitzgerald, Katherine A. .

NATURE IMMUNOLOGY, 2010, 11 (05) :395-403

[70] HIN-200 Proteins Regulate Caspase Activation in Response to Foreign Cytoplasmic DNA [J].

Roberts, Tara L. ;

Idris, Adi ;

Dunn, Jasmyn A. ;

Kelly, Greg M. ;

Burnton, Carol M. ;

Hodgson, Samantha ;

Hardy, Lani L. ;

Garceau, Valerie ;

Sweet, Matthew J. ;

Ross, Ian L. ;

Hume, David A. ;

Stacey, Katryn J. .

SCIENCE, 2009, 323 (5917) :1057-1060

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