Title | N-terminal degradation activates the NLRP1B inflammasome. |
Publication Type | Journal Article |
Year of Publication | 2019 |
Authors | Chui AJ, Okondo MC, Rao SD, Gai K, Griswold AR, Johnson DC, Ball DP, Taabazuing CY, Orth EL, Vittimberga BA, Bachovchin DA |
Journal | Science |
Volume | 364 |
Issue | 6435 |
Pagination | 82-85 |
Date Published | 2019 04 05 |
ISSN | 1095-9203 |
Keywords | Animals, Antigens, Bacterial, Apoptosis Regulatory Proteins, Bacterial Toxins, Caspase 1, CRISPR-Cas Systems, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases, Gene Knockout Techniques, HEK293 Cells, Host-Pathogen Interactions, Humans, Immunity, Innate, Inflammasomes, Mice, Proteasome Endopeptidase Complex, Proteolysis, Pyroptosis, RAW 264.7 Cells, Serine Proteinase Inhibitors, THP-1 Cells, Ubiquitin-Protein Ligases |
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 |
Alternate Journal | Science |
PubMed ID | 30872531 |
PubMed Central ID | PMC6610862 |
Grant List | P30 CA008748 / CA / NCI NIH HHS / United States R01 AI137168 / AI / NIAID NIH HHS / United States T32 GM007739 / GM / NIGMS NIH HHS / United States T32 GM115327 / GM / NIGMS NIH HHS / United States |
Submitted by api_import on April 30, 2019 - 4:34pm