Anthrax Lethal Factor Cleavage of Nlrp1 Is Required for Activation of the Inflammasome

被引：254

作者：

Levinsohn, Jonathan L. ^{[1
]}

Newman, Zachary L. ^{[1
]}

Hellmich, Kristina A. ^{[1
]}

Fattah, Rasem ^{[1
]}

Getz, Matthew A. ^{[1
]}

Liu, Shihui ^{[1
]}

Sastalla, Inka ^{[1
]}

Leppla, Stephen H. ^{[1
]}

Moayeri, Mahtab ^{[1
]}

机构：

[1] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA

来源：

PLOS PATHOGENS | 2012年 / 8卷 / 03期

关键词：

CASPASE-1; ACTIVATION; TOXIN; PROTEOLYSIS; KINASE;

D O I：

10.1371/journal.ppat.1002638

中图分类号：

Q93 [微生物学];

学科分类号：

071005 ; 100705 ;

摘要：

NOD-like receptor (NLR) proteins (Nlrps) are cytosolic sensors responsible for detection of pathogen and danger-associated molecular patterns through unknown mechanisms. Their activation in response to a wide range of intracellular danger signals leads to formation of the inflammasome, caspase-1 activation, rapid programmed cell death (pyroptosis) and maturation of IL-1 beta and IL-18. Anthrax lethal toxin (LT) induces the caspase-1-dependent pyroptosis of mouse and rat macrophages isolated from certain inbred rodent strains through activation of the NOD-like receptor (NLR) Nlrp1 inflammasome. Here we show that LT cleaves rat Nlrp1 and this cleavage is required for toxin-induced inflammasome activation, IL-1 beta release, and macrophage pyroptosis. These results identify both a previously unrecognized mechanism of activation of an NLR and a new, physiologically relevant protein substrate of LT.

引用

页数：7

共 20 条

[11] Anthrax lethal toxin kills macrophages in a strain-specific manner by apoptosis or caspase-1-mediated necrosis [J].

Muehlbauer, Stefan M. ;

Evering, Teresa H. ;

Bonuccelli, Gloria ;

Squires, Raynal C. ;

Ashton, Anthony W. ;

Porcelli, Steven A. ;

Lisanti, Michael P. ;

Brojatsch, Jurgen .

CELL CYCLE, 2007, 6 (06) :758-766

[12] Anthrax lethal toxin activates the inflammasome in sensitive rat macrophages [J].

Newman, Zachary L. ;

Crown, Devorah ;

Leppla, Stephen H. ;

Moayeri, Mahtab .

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2010, 398 (04) :785-789

[13] Susceptibility to Anthrax Lethal Toxin-Induced Rat Death Is Controlled by a Single Chromosome 10 Locus That Includes rNlrp1 [J].

Newman, Zachary L. ;

Printz, Morton P. ;

Liu, Shihui ;

Crown, Devorah ;

Breen, Laura ;

Miller-Randolph, Sharmina ;

Flodman, Pamela ;

Leppla, Stephen H. ;

Moayeri, Mahtab .

PLOS PATHOGENS, 2010, 6 (05) :1-8

[14] CA-074Me Protection against Anthrax Lethal Toxin [J].

Newman, Zachary L. ;

Leppla, Stephen H. ;

Moayeri, Mahtab .

INFECTION AND IMMUNITY, 2009, 77 (10) :4327-4336

[15]

Park S, 2000, PROTEIN EXPRES PURIF, V18, P293, DOI 10.1080/02726350008906840

[16] Proteasomes control caspase-1 activation in anthrax lethal toxin-mediated cell killing [J].

Squires, Raynal C. ;

Muehlbauer, Stefan M. ;

Brojatsch, Juergen .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2007, 282 (47) :34260-34267

[17] The structural basis for substrate and inhibitor selectivity of the anthrax lethal factor [J].

Turk, BE ;

Wong, TY ;

Schwarzenbacher, R ;

Jarrell, ET ;

Leppla, SH ;

Collier, RJ ;

Liddington, RC ;

Cantley, LC .

NATURE STRUCTURAL & MOLECULAR BIOLOGY, 2004, 11 (01) :60-66

[18] Susceptibility of mitogen-activated protein kinase kinase family members to proteolysis by anthrax lethal factor [J].

Vitale, G ;

Bernardi, L ;

Napolitani, G ;

Mock, M ;

Montecucco, C .

BIOCHEMICAL JOURNAL, 2000, 352 :739-745

[19] Anthrax lethal toxin-induced inflammasome formation and caspase-1 activation are late events dependent on ion fluxes and the proteasome [J].

Wickliffe, Katherine E. ;

Leppla, Stephen H. ;

Moayeri, Mahtab .

CELLULAR MICROBIOLOGY, 2008, 10 (02) :332-343

[20] The NLRC4 inflammasome receptors for bacterial flagellin and type III secretion apparatus [J].

Zhao, Yue ;

Yang, Jieling ;

Shi, Jianjin ;

Gong, Yi-Nan ;

Lu, Qiuhe ;

Xu, Hao ;

Liu, Liping ;

Shao, Feng .

NATURE, 2011, 477 (7366) :596-U257

← 1 2 →