N-terminal degradation activates the NLRP1B inflammasome.
| Publication Type | Academic Article |
| Authors | Chui A, Okondo M, Rao S, Gai K, Griswold A, Johnson D, Ball D, Taabazuing C, Orth E, Vittimberga B, Bachovchin D |
| Journal | Science |
| Volume | 364 |
| Issue | 6435 |
| Pagination | 82-85 |
| Date Published | 03/14/2019 |
| ISSN | 1095-9203 |
| Keywords | Antigens, Bacterial, Apoptosis Regulatory Proteins, Bacterial Toxins, Inflammasomes, Proteolysis, Pyroptosis |
| 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. |
| DOI | 10.1126/science.aau1208 |
| PubMed ID | 30872531 |
| PubMed Central ID | PMC6610862 |