Protein folding stress potentiates NLRP1 and CARD8 inflammasome activation Journal Article
| Authors: | Orth-He, E. L.; Huang, H. C.; Rao, S. D.; Wang, Q.; Chen, Q.; O'Mara, C. M.; Chui, A. J.; Saoi, M.; Griswold, A. R.; Bhattacharjee, A.; Ball, D. P.; Cross, J. R.; Bachovchin, D. A. |
| Article Title: | Protein folding stress potentiates NLRP1 and CARD8 inflammasome activation |
| Abstract: | NLRP1 and CARD8 are related pattern-recognition receptors (PRRs) that detect intracellular danger signals and form inflammasomes. Both undergo autoproteolysis, generating N-terminal (NT) and C-terminal (CT) fragments. The proteasome-mediated degradation of the NT releases the CT from autoinhibition, but the stimuli that trigger NT degradation have not been fully elucidated. Here, we show that several distinct agents that interfere with protein folding, including aminopeptidase inhibitors, chaperone inhibitors, and inducers of the unfolded protein response, accelerate NT degradation. However, these agents alone do not trigger inflammasome formation because the released CT fragments are physically sequestered by the serine dipeptidase DPP9. We show that DPP9-binding ligands must also be present to disrupt these complexes and allow the CT fragments to oligomerize into inflammasomes. Overall, these results indicate that NLRP1 and CARD8 detect a specific perturbation that induces both protein folding stress and DPP9 ligand accumulation. © 2022 The Authors |
| Keywords: | metabolism; apoptosis regulatory proteins; peptides; adaptor proteins, signal transducing; protein folding; signal transducing adaptor protein; apoptosis regulatory protein; caspase recruitment domain signaling protein; nucleotide binding oligomerization domain like receptor; inflammasome; card signaling adaptor proteins; inflammasomes; aminopeptidases; dpp8/9; nlrp1; card8; nlr proteins; cp: immunology |
| Journal Title: | Cell Reports |
| Volume: | 42 |
| Issue: | 1 |
| ISSN: | 2211-1247 |
| Publisher: | Cell Press |
| Date Published: | 2023-01-31 |
| Start Page: | 111965 |
| Language: | English |
| DOI: | 10.1016/j.celrep.2022.111965 |
| PUBMED: | 36649711 |
| PROVIDER: | scopus |
| PMCID: | PMC10042216 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Corresponding author is MSK author: Daniel A. Bachovchin -- Source: Scopus |
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