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M24B aminopeptidase inhibitors selectively activate the CARD8 inflammasome.

TitleM24B aminopeptidase inhibitors selectively activate the CARD8 inflammasome.
Publication TypeJournal Article
Year of Publication2022
AuthorsRao SD, Chen Q, Wang Q, Orth-He EL, Saoi M, Griswold AR, Bhattacharjee A, Ball DP, Huang H-C, Chui AJ, Covelli DJ, You S, Cross JR, Bachovchin DA
JournalNat Chem Biol
Date Published2022 Feb 14
ISSN1552-4469
Abstract

Inflammasomes are multiprotein complexes that sense intracellular danger signals and induce pyroptosis. CARD8 and NLRP1 are related inflammasomes that are repressed by the enzymatic activities and protein structures of the dipeptidyl peptidases 8 and 9 (DPP8/9). Potent DPP8/9 inhibitors such as Val-boroPro (VbP) activate both NLRP1 and CARD8, but chemical probes that selectively activate only one have not been identified. Here we report a small molecule called CQ31 that selectively activates CARD8. CQ31 inhibits the M24B aminopeptidases prolidase (PEPD) and Xaa-Pro aminopeptidase 1 (XPNPEP1), leading to the accumulation of proline-containing peptides that inhibit DPP8/9 and thereby activate CARD8. NLRP1 is distinct from CARD8 in that it directly contacts DPP8/9's active site; these proline-containing peptides, unlike VbP, do not disrupt this repressive interaction and thus do not activate NLRP1. We expect that CQ31 will now become a valuable tool to study CARD8 biology.

DOI10.1038/s41589-021-00964-7
Alternate JournalNat Chem Biol
PubMed ID35165443
Grant ListT32 GM115327-Tan / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) /
F30 CA008748 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) /
T32 GM007739-Andersen / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) /
R25AI140472 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) /
R01 AI163170 / AI / NIAID NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
N/A / / Pew Charitable Trusts /
N/A / / Gabrielle's Angel Foundation for Cancer Research (Gabrielle's Angel Foundation) /

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