The NLRP1 and CARD8 inflammasomes detect reductive stress Journal Article
| Authors: | Wang, Q.; Hsiao, J. C.; Yardeny, N.; Huang, H. C.; O'Mara, C. M.; Orth-He, E. L.; Ball, D. P.; Zhang, Z.; Bachovchin, D. A. |
| Article Title: | The NLRP1 and CARD8 inflammasomes detect reductive stress |
| Abstract: | The danger signals that activate the related nucleotide-binding domain leucine-rich repeat pyrin domain-containing 1 (NLRP1) and caspase activation and recruitment domain-containing 8 (CARD8) inflammasomes have not been fully established. We recently reported that the oxidized form of TRX1 binds to NLRP1 and represses inflammasome activation. These findings suggested that intracellular reductive stress, which would reduce oxidized TRX1 and thereby abrogate the NLRP1-TRX1 interaction, is an NLRP1 inflammasome-activating danger signal. However, no agents that induce reductive stress were known to test this premise. Here, we identify and characterize several radical-trapping antioxidants, including JSH-23, that induce reductive stress. We show that these compounds accelerate the proteasome-mediated degradation of the repressive N-terminal fragments of both NLRP1 and CARD8, releasing the inflammasome-forming C-terminal fragments from autoinhibition. Overall, this work validates chemical probes that induce reductive stress and establishes reductive stress as a danger signal sensed by both the NLRP1 and CARD8 inflammasomes. © 2022 The Authors |
| Keywords: | metabolism; cell death; apoptosis regulatory proteins; adaptor proteins, signal transducing; signal transducing adaptor protein; apoptosis regulatory protein; nucleotide binding oligomerization domain like receptor; inflammasome; inflammasomes; nlrp1; card8; nlr proteins; cp: immunology; jsh-23; reductive stress |
| Journal Title: | Cell Reports |
| Volume: | 42 |
| Issue: | 1 |
| ISSN: | 2211-1247 |
| Publisher: | Cell Press |
| Date Published: | 2023-01-31 |
| Start Page: | 111966 |
| Language: | English |
| DOI: | 10.1016/j.celrep.2022.111966 |
| PUBMED: | 36649710 |
| PROVIDER: | scopus |
| PMCID: | PMC9942139 |
| 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 |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work