Division of Immunology and Pathogenesis, Department of Molecular & Cell Biology, and Cancer Research Laboratory, University of California, Berkeley, CA, USA.
Howard Hughes Medical Institute, University of California, Berkeley, CA, USA.
Science. 2019 Apr 5;364(6435). doi: 10.1126/science.aau1330. Epub 2019 Mar 14.
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 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.
炎症小体是多蛋白平台，通过募集和激活半胱天冬酶-1 来启动先天免疫。NLRP1B 炎症小体在炭疽致死毒素蛋白酶的直接切割作用下被激活。然而，切割导致 NLRP1B 激活的机制尚不清楚。在这项研究中，我们发现切割导致蛋白酶体介导的 NLRP1B 氨基末端结构域的降解，释放出一个羧基末端片段，该片段是一种有效的半胱天冬酶-1 激活剂。蛋白酶体介导的 NLRP1B 降解对于 NLRP1B 的激活是必需且充分的。与我们的功能降解模型一致，我们鉴定出 IpaH7.8，一种泛素连接酶分泌效应子，是诱导 NLRP1B 降解和激活的酶。我们的结果为不同病原体编码的酶活性激活 NLRP1B 提供了一个统一的机制。
