N-terminal degradation activates the NLRP1B inflammasome

被引：230

作者：

Chui, Ashley J. ^{[1
]}

Okondo, Marian C. ^{[2
]}

Rao, Sahana D. ^{[1
]}

Gai, Kuo ^{[2
]}

Griswold, Andrew R. ^{[3
]}

Johnson, Darren C. ^{[1
]}

Ball, Daniel P. ^{[2
]}

Taabazuing, Cornelius Y. ^{[2
]}

Orth, Elizabeth L. ^{[1
]}

Vittimberga, Brooke A. ^{[2
]}

Bachovchin, Daniel A. ^{[1
,2
,3
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Triinst PhD Program Chem Biol, New York, NY 10065 USA

[2] Mem Sloan Kettering Canc Ctr, Chem Biol Program, New York, NY 10065 USA

[3] Mem Sloan Kettering Canc Ctr, Weill Cornell Grad Sch Med Sci, Pharmacol Program, New York, NY 10065 USA

来源：

SCIENCE | 2019年 / 364卷 / 6435期

关键词：

ANTHRAX LETHAL TOXIN; END RULE PATHWAY; INHIBITION; CYTOTOXICITY;

D O I：

10.1126/science.aau1208

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：

Intracellular pathogens and danger signals trigger the formation of inflammasomes, which activate inflammatory caspases and induce pyroptosis. The anthrax lethal factor metalloprotease and small-molecule DPP8/9 inhibitors both activate the NLRP1B inflammasome, but the molecular mechanism of NLRP1B activation is unknown. In this study, we used genome-wide CRISPR-Cas9 knockout screens to identify genes required for NLRP1B-mediated pyroptosis. We discovered that lethal factor induces cell death via the N-end rule proteasomal degradation pathway. Lethal factor directly cleaves NLRP1B, inducing the N-end rule-mediated degradation of the NLRP1B N terminus and freeing the NLRP1B C terminus to activate caspase-1. DPP8/9 inhibitors also induce proteasomal degradation of the NLRP1B N terminus but not via the N-end rule pathway. Thus, N-terminal degradation is the common activation mechanism of this innate immune sensor.

引用

页码：82 / +

页数：34

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