Functional degradation: A mechanism of NLRP1 inflammasome activation by diverse pathogen enzymes

被引：277
作者：
Sandstrom, Andrew [1 ,2 ,3 ]
Mitchell, Patrick S. [1 ,2 ]
Goers, Lisa [4 ,5 ,6 ]
Mu, Edward W. [1 ,2 ]
Lesser, Cammie F. [4 ,5 ,6 ]
Vance, Russell E. [1 ,2 ,3 ]
机构：
[1] Univ Calif Berkeley, Dept Mol & Cell Biol, Div Immunol & Pathogenesis, 229 Stanley Hall, Berkeley, CA 94720 USA
[2] Univ Calif Berkeley, Canc Res Lab, Berkeley, CA 94720 USA
[3] Univ Calif Berkeley, Howard Hughes Med Inst, Berkeley, CA 94720 USA
[4] Harvard Med Sch, Dept Microbiol, Boston, MA 02115 USA
[5] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA
[6] Massachusetts Gen Hosp, Dept Med, Div Infect Dis, Boston, MA 02114 USA
来源：
SCIENCE | 2019年 / 364卷 / 6435期
关键词：
ANTHRAX LETHAL TOXIN; CASPASE-1; ACTIVATION; UBIQUITIN LIGASES; RHO GTPASES; CELL-DEATH; PROTEIN; MOUSE; SUSCEPTIBILITY; RECOGNITION; BACTERIA;
D O I：
10.1126/science.aau1330
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 multiprotein platforms that initiate innate immunity by recruitment and activation of caspase-1. The NLRP1B inflammasome is activated upon direct cleavage by the anthrax lethal toxin protease. However, the mechanism by which cleavage results in NLRP1B activation is unknown. In this study, we find that cleavage results in proteasome-mediated degradation of the amino-terminal domains of NLRP1B, liberating a carboxyl-terminal fragment that is a potent caspase-1 activator. Proteasome-mediated degradation of NLRP1B is both necessary and sufficient for NLRP1B activation. Consistent with our functional degradation model, we identify IpaH7.8, a Shigella flexneri ubiquitin ligase secreted effector, as an enzyme that induces NLRP1B degradation and activation. Our results provide a unified mechanism for NLRP1B activation by diverse pathogen-encoded enzymatic activities.
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页码：42 / +
页数：26
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