Title | DPP9's Enzymatic Activity and Not Its Binding to CARD8 Inhibits Inflammasome Activation. |
Publication Type | Journal Article |
Year of Publication | 2019 |
Authors | Griswold AR, Ball DP, Bhattacharjee A, Chui AJ, Rao SD, Taabazuing CY, Bachovchin DA |
Journal | ACS Chem Biol |
Volume | 14 |
Issue | 11 |
Pagination | 2424-2429 |
Date Published | 2019 Nov 15 |
ISSN | 1554-8937 |
Abstract | Inflammasomes are multiprotein complexes formed in response to pathogens. NLRP1 and CARD8 are related proteins that form inflammasomes, but the pathogen-associated signal(s) and the molecular mechanisms controlling their activation have not been established. Inhibitors of the serine dipeptidyl peptidases DPP8 and DPP9 (DPP8/9) activate both NLRP1 and CARD8. Interestingly, DPP9 binds directly to NLRP1 and CARD8, and this interaction may contribute to the inhibition of NLRP1. Here, we use activity-based probes, reconstituted inflammasome assays, and mass spectrometry-based proteomics to further investigate the DPP9-CARD8 interaction. We show that the DPP9-CARD8 interaction, unlike the DPP9-NLRP1 interaction, is not disrupted by DPP9 inhibitors or CARD8 mutations that block autoproteolysis. Moreover, wild-type, but not catalytically inactive mutant, DPP9 rescues CARD8-mediated cell death in knockout cells. Together, this work reveals that DPP9's catalytic activity and not its binding to CARD8 restrains the CARD8 inflammasome and thus suggests the binding interaction likely serves some other biological purpose. |
DOI | 10.1021/acschembio.9b00462 |
Alternate Journal | ACS Chem. Biol. |
PubMed ID | 31525884 |
PubMed Central ID | PMC6862324 |
Grant List | F30 CA243444 / CA / NCI NIH HHS / United States P30 CA008748 / CA / NCI NIH HHS / United States R01 AI137168 / AI / NIAID NIH HHS / United States T32 GM007739 / GM / NIGMS NIH HHS / United States |
Submitted by api_import on October 31, 2019 - 4:04pm