Cargando…
DPP9’s Enzymatic Activity and Not Its Binding to CARD8 Inhibits Inflammasome Activation
[Image: see text] 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 serin...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical
Society
2019
|
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6862324/ https://www.ncbi.nlm.nih.gov/pubmed/31525884 http://dx.doi.org/10.1021/acschembio.9b00462 |
_version_ | 1783471528565800960 |
---|---|
author | Griswold, Andrew R. Ball, Daniel P. Bhattacharjee, Abir Chui, Ashley J. Rao, Sahana D. Taabazuing, Cornelius Y. Bachovchin, Daniel A. |
author_facet | Griswold, Andrew R. Ball, Daniel P. Bhattacharjee, Abir Chui, Ashley J. Rao, Sahana D. Taabazuing, Cornelius Y. Bachovchin, Daniel A. |
author_sort | Griswold, Andrew R. |
collection | PubMed |
description | [Image: see text] 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. |
format | Online Article Text |
id | pubmed-6862324 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | American Chemical
Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-68623242019-11-20 DPP9’s Enzymatic Activity and Not Its Binding to CARD8 Inhibits Inflammasome Activation Griswold, Andrew R. Ball, Daniel P. Bhattacharjee, Abir Chui, Ashley J. Rao, Sahana D. Taabazuing, Cornelius Y. Bachovchin, Daniel A. ACS Chem Biol [Image: see text] 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. American Chemical Society 2019-09-17 2019-11-15 /pmc/articles/PMC6862324/ /pubmed/31525884 http://dx.doi.org/10.1021/acschembio.9b00462 Text en Copyright © 2019 American Chemical Society This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) , which permits copying and redistribution of the article or any adaptations for non-commercial purposes. |
spellingShingle | Griswold, Andrew R. Ball, Daniel P. Bhattacharjee, Abir Chui, Ashley J. Rao, Sahana D. Taabazuing, Cornelius Y. Bachovchin, Daniel A. DPP9’s Enzymatic Activity and Not Its Binding to CARD8 Inhibits Inflammasome Activation |
title | DPP9’s Enzymatic Activity and Not Its Binding
to CARD8 Inhibits Inflammasome Activation |
title_full | DPP9’s Enzymatic Activity and Not Its Binding
to CARD8 Inhibits Inflammasome Activation |
title_fullStr | DPP9’s Enzymatic Activity and Not Its Binding
to CARD8 Inhibits Inflammasome Activation |
title_full_unstemmed | DPP9’s Enzymatic Activity and Not Its Binding
to CARD8 Inhibits Inflammasome Activation |
title_short | DPP9’s Enzymatic Activity and Not Its Binding
to CARD8 Inhibits Inflammasome Activation |
title_sort | dpp9’s enzymatic activity and not its binding
to card8 inhibits inflammasome activation |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6862324/ https://www.ncbi.nlm.nih.gov/pubmed/31525884 http://dx.doi.org/10.1021/acschembio.9b00462 |
work_keys_str_mv | AT griswoldandrewr dpp9senzymaticactivityandnotitsbindingtocard8inhibitsinflammasomeactivation AT balldanielp dpp9senzymaticactivityandnotitsbindingtocard8inhibitsinflammasomeactivation AT bhattacharjeeabir dpp9senzymaticactivityandnotitsbindingtocard8inhibitsinflammasomeactivation AT chuiashleyj dpp9senzymaticactivityandnotitsbindingtocard8inhibitsinflammasomeactivation AT raosahanad dpp9senzymaticactivityandnotitsbindingtocard8inhibitsinflammasomeactivation AT taabazuingcorneliusy dpp9senzymaticactivityandnotitsbindingtocard8inhibitsinflammasomeactivation AT bachovchindaniela dpp9senzymaticactivityandnotitsbindingtocard8inhibitsinflammasomeactivation |