Functional degradation: A mechanism of NLRP1 inflammasome activation by diverse pathogen enzymes
2019; American Association for the Advancement of Science; Volume: 364; Issue: 6435 Linguagem: Inglês
10.1126/science.aau1330
ISSN1095-9203
AutoresAndrew Sandstrom, Patrick S. Mitchell, Lisa Goers, Edward Mu, Cammie F. Lesser, Russell E. Vance,
Tópico(s)Heme Oxygenase-1 and Carbon Monoxide
ResumoInflammasomes 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.
Referência(s)