N-terminal degradation activates the NLRP1B inflammasome Journal Article
| Authors: | Chui, A. J.; Okondo, M. C.; Rao, S. D.; Gai, K.; Griswold, A. R.; Johnson, D. C.; Ball, D. P.; Taabazuing, C. Y.; Orth, E. L.; Vittimberga, B. A.; Bachovchin, D. A. |
| Article Title: | N-terminal degradation activates the NLRP1B inflammasome |
| Abstract: | 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. 2017 © The Authors. |
| Journal Title: | Science |
| Volume: | 364 |
| Issue: | 6435 |
| ISSN: | 0036-8075 |
| Publisher: | American Association for the Advancement of Science |
| Date Published: | 2019-04-05 |
| Start Page: | 82 |
| End Page: | 85 |
| Language: | English |
| DOI: | 10.1126/science.aau1208 |
| PUBMED: | 30872531 |
| PROVIDER: | scopus |
| PMCID: | PMC6610862 |
| DOI/URL: | |
| Notes: | Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
Related MSK Work