DPP9's enzymatic activity and not its binding to CARD8 inhibits inflammasome activation Journal Article

   


Authors: Griswold, A. R.; Ball, D. P.; Bhattacharjee, A.; Chui, A. J.; Rao, S. D.; Taabazuing, C. Y.; Bachovchin, D. A.
Article Title: DPP9's enzymatic activity and not its binding to CARD8 inhibits inflammasome activation
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 DPP9 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. © 2019 American Chemical Society.
Keywords: protein expression; unclassified drug; human cell; nonhuman; mouse; cell death; protein protein interaction; protein binding; enzyme activity; proteomics; immunoprecipitation; catalysis; inflammasome; human; priority journal; article; hek293t cell line; card8 protein; dipeptidyl peptidase; dipeptidyl peptidase 8; dipeptidyl peptidase 9; nlrp1 protein
Journal Title: ACS Chemical Biology
Volume: 14
Issue: 11
ISSN: 1554-8929
Publisher: American Chemical Society  
Date Published: 2019-11-15
Start Page: 2424
End Page: 2429
Language: English
DOI: 10.1021/acschembio.9b00462
PUBMED: 31525884
PROVIDER: scopus
PMCID: PMC6862324
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85073588883&doi=10.1021%2facschembio.9b00462&partnerID=40&md5=b4fe9680ccfd26ca155d67298682884f
Notes: Source: Scopus
Altmetric
What is Altmetric?
Citation Impact
What is Dimensions Citation Badge?
BMJ Impact Analytics
MSK Authors
  1. Daniel Bachovchin
    35 Bachovchin
  2. Cornelius Y Taabazuing
    9 Taabazuing
  3. Sahana Dinesh Rao
    13 Rao
  4. Ashley Jeng-yun Chui
    11 Chui
  5. Andrew Griswold
    14 Griswold
  6. Daniel Parker Ball
    14 Ball
  7. Abir Bhattacharjee
    5 Bhattacharjee
Related MSK Work