The interaction between NLRP1 and oxidized TRX1 involves a transient disulfide bond Journal Article
| Authors: | Geeson, M. B.; Hsiao, J. C.; Tsamouri, L. P.; Ball, D. P.; Bachovchin, D. A. |
| Article Title: | The interaction between NLRP1 and oxidized TRX1 involves a transient disulfide bond |
| Abstract: | NLRP1 is an innate immune receptor that detects pathogen-associated signals, assembles into a multiprotein structure called an inflammasome, and triggers a proinflammatory form of cell death called pyroptosis. We previously discovered that the oxidized, but not the reduced, form of thioredoxin-1 directly binds to NLRP1 and represses inflammasome formation. However, the molecular basis for NLRP1’s selective association with only the oxidized form of TRX1 has not yet been established. Here, we leveraged AlphaFold-Multimer, site-directed mutagenesis, thiol-trapping experiments, and mass spectrometry to reveal that a specific cysteine residue (C427 in humans) on NLRP1 forms a transient disulfide bond with oxidized TRX1. Overall, this work demonstrates how NLRP1 monitors the cellular redox state, further illuminating an unexpected connection between the intracellular redox potential and the innate immune system. © 2023 Elsevier Ltd |
| Keywords: | controlled study; unclassified drug; human cell; nonhuman; mutant protein; binding affinity; mass spectrometry; animal cell; mouse; metabolism; cell death; protein protein interaction; apoptosis regulatory proteins; wild type; keratinocyte; chemistry; sequence alignment; immunoprecipitation; immunoblotting; adaptor proteins, signal transducing; innate immunity; site directed mutagenesis; molecular weight; signal transducing adaptor protein; polymer; oxidation reduction reaction; oxidation-reduction; disulfide; disulfides; cysteine; apoptosis regulatory protein; polyacrylamide gel electrophoresis; hek293 cells; thioredoxin; nucleotide binding oligomerization domain like receptor; hydrophobicity; liquid chromatography-mass spectrometry; transient expression; thiol; disulfide bond; pattern recognition receptor; pyroptosis; inflammasome; redox; inflammasomes; humans; human; article; thiol group; oxidation reduction potential; n ethylmaleimide; hek293t cell line; thp-1 cell line; iodoacetamide; nlrp1 protein; nlrp1; nlrp1 protein, human; nlr proteins; thioredoxins; hek293s cell line; alphafold-multimer; thioredoxin 1 |
| Journal Title: | Cell Chemical Biology |
| Volume: | 31 |
| Issue: | 5 |
| ISSN: | 2451-9456 |
| Publisher: | Cell Press |
| Date Published: | 2024-05-16 |
| Start Page: | 955 |
| End Page: | 961.e4 |
| Language: | English |
| DOI: | 10.1016/j.chembiol.2023.12.012 |
| PUBMED: | 38215746 |
| PROVIDER: | scopus |
| PMCID: | PMC11102328 |
| 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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6Hsiao -
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2Geeson
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