M24B aminopeptidase inhibitors selectively activate the CARD8 inflammasome Journal Article


Authors: Rao, S. D.; Chen, Q.; Wang, Q.; Orth-He, E. L.; Saoi, M.; Griswold, A. R.; Bhattacharjee, A.; Ball, D. P.; Huang, H. C.; Chui, A. J.; Covelli, D. J.; You, S.; Cross, J. R.; Bachovchin, D. A.
Article Title: M24B aminopeptidase inhibitors selectively activate the CARD8 inflammasome
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. [Figure not available: see fulltext.] © 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.
Keywords: neoplasm proteins; apoptosis regulatory proteins; tumor protein; apoptosis regulatory protein; proline; caspase recruitment domain signaling protein; aminopeptidase; inflammasome; card signaling adaptor proteins; inflammasomes; aminopeptidases
Journal Title: Nature Chemical Biology
Volume: 18
Issue: 5
ISSN: 1552-4450
Publisher: Nature Publishing Group  
Date Published: 2022-05-01
Start Page: 565
End Page: 574
Language: English
DOI: 10.1038/s41589-021-00964-7
PUBMED: 35165443
PROVIDER: scopus
PMCID: PMC9179932
DOI/URL:
Notes: Article -- Export Date: 1 June 2022 -- Source: Scopus
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MSK Authors
  1. Justin Robert Cross
    111 Cross
  2. Sahana Dinesh Rao
    13 Rao
  3. Ashley Jeng-yun Chui
    11 Chui
  4. Daniel Parker Ball
    14 Ball
  5. Elizabeth Lucille Orth
    10 Orth
  6. Hsin-Che Huang
    12 Huang
  7. Qinghui Wang
    8 Wang
  8. Michelle Saoi
    8 Saoi
  9. Qifeng Chen
    3 Chen
  10. Shaochen You
    1 You