publication . Other literature type . Article . 2019

DPP9’s Enzymatic Activity and Not Its Bindingto CARD8 Inhibits Inflammasome Activation

Abir Bhattacharjee; Daniel A. Bachovchin; Daniel A. Bachovchin; Cornelius Y. Taabazuing; Sahana D. Rao; Andrew R. Griswold; Andrew R. Griswold; Daniel P. Ball; Ashley J. Chui;
Open Access
  • Published: 17 Sep 2019
  • Publisher: American Chemical Society (ACS)
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 in...
Subjects
free text keywords: Letters, Molecular Medicine, Biochemistry, General Medicine, NLRP1, Programmed cell death, Inflammasome, medicine.drug, medicine, Serine, Cell biology, Chemistry, Enzyme, chemistry.chemical_classification, Proteomics, Mutant
Funded by
NIH| Weill Cornell/Rockefeller/Sloan-Kettering MST Program
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 5T32GM007739-30
  • Funding stream: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
,
NIH| MOUSE GENETICS
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 2P30CA008748-43
  • Funding stream: NATIONAL CANCER INSTITUTE
,
NIH| Characterizing the Mechanism of DPP8/9 Inhibitor-Induced Pyroptosis
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 1R01AI137168-01
  • Funding stream: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
30 references, page 1 of 2

Janeway C. A.Jr.; Medzhitov R. (2002) Innate immune recognition. Annu. Rev. Immunol. 20, 197–216. 10.1146/annurev.immunol.20.083001.084359.11861602 [OpenAIRE] [PubMed] [DOI]

Broz P.; Dixit V. M. (2016) Inflammasomes: mechanism of assembly, regulation and signalling. Nat. Rev. Immunol. 16, 407–420. 10.1038/nri.2016.58.27291964 [OpenAIRE] [PubMed] [DOI]

Lamkanfi M.; Dixit V. M. (2014) Mechanisms and functions of inflammasomes. Cell 157, 1013–1022. 10.1016/j.cell.2014.04.007.24855 941 [OpenAIRE] [PubMed] [DOI]

Martinon F.; Burns K.; Tschopp J. (2002) The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol. Cell 10, 417–426. 10.1016/S1097-2765(02)00599-3.12191486 [PubMed] [DOI]

D’Osualdo A.; Weichenberger C. X.; Wagner R. N.; Godzik A.; Wooley J.; Reed J. C. (2011) CARD8 and NLRP1 undergo autoproteolytic processing through a ZU5-like domain. PLoS One 6, e27396 10.1371/journal.pone.0027396.22087307 [OpenAIRE] [PubMed] [DOI]

Finger J. N.; Lich J. D.; Dare L. C.; Cook M. N.; Brown K. K.; Duraiswami C.; Bertin J.; Gough P. J. (2012) Autolytic proteolysis within the function to find domain (FIIND) is required for NLRP1 inflammasome activity. J. Biol. Chem. 287, 25030–25037. 10.1074/jbc.M112.378323.22665479 [OpenAIRE] [PubMed] [DOI]

Frew B. C.; Joag V. R.; Mogridge J. (2012) Proteolytic processing of Nlrp1b is required for inflammasome activity. PLoS Pathog. 8, e1002659 10.1371/journal.ppat.1002659.22536155 [OpenAIRE] [PubMed] [DOI]

Boyden E. D.; Dietrich W. F. (2006) Nalp1b controls mouse macrophage susceptibility to anthrax lethal toxin. Nat. Genet. 38, 240–244. 10.1038/ng1724.16429160 [OpenAIRE] [PubMed] [DOI]

Levinsohn J. L.; Newman Z. L.; Hellmich K. A.; Fattah R.; Getz M. A.; Liu S.; Sastalla I.; Leppla S. H.; Moayeri M. (2012) Anthrax lethal factor cleavage of Nlrp1 is required for activation of the inflammasome. PLoS Pathog. 8, e1002638 10.1371/journal.ppat.1002638.22479187 [OpenAIRE] [PubMed] [DOI]

Hellmich K. A.; Levinsohn J. L.; Fattah R.; Newman Z. L.; Maier N.; Sastalla I.; Liu S.; Leppla S. H.; Moayeri M. (2012) Anthrax lethal factor cleaves mouse nlrp1b in both toxin-sensitive and toxin-resistant macrophages. PLoS One 7, e49741 10.1371/journal.pone.0049741.23152930 [OpenAIRE] [PubMed] [DOI]

Chavarria-Smith J.; Vance R. E. (2013) Direct proteolytic cleavage of NLRP1B is necessary and sufficient for inflammasome activation by anthrax lethal factor. PLoS Pathog. 9, e1003452 10.1371/journal.ppat.1003452.23818853 [OpenAIRE] [PubMed] [DOI]

Sandstrom A.; Mitchell P. S.; Goers L.; Mu E. W.; Lesser C. F.; Vance R. E. (2019) Functional degradation: A mechanism of NLRP1 inflammasome activation by diverse pathogen enzymes. Science 364, eaau1330 10.1126/science.aau1330.30872533 [OpenAIRE] [PubMed] [DOI]

Chui A. J.; Okondo M. C.; Rao S. D.; Gai K.; Griswold A. R.; Johnson D. C.; Ball D. P.; Taabazuing C. Y.; Orth E. L.; Vittimberga B. A.; Bachovchin D. A. (2019) N-terminal degradation activates the NLRP1B inflammasome. Science 364, 82–85. 10.1126/science.aau1208.30872531 [OpenAIRE] [PubMed] [DOI]

Ewald S. E.; Chavarria-Smith J.; Boothroyd J. C. (2014) NLRP1 is an inflammasome sensor for Toxoplasma gondii. Infect. Immun. 82, 460–468. 10.1128/IAI.01170-13.24218483 [OpenAIRE] [PubMed] [DOI]

Cirelli K. M.; Gorfu G.; Hassan M. A.; Printz M.; Crown D.; Leppla S. H.; Grigg M. E.; Saeij J. P.; Moayeri M. (2014) Inflammasome sensor NLRP1 controls rat macrophage susceptibility to Toxoplasma gondii. PLoS Pathog. 10, e1003927 10.1371/journal.ppat.1003927.24626226 [OpenAIRE] [PubMed] [DOI]

30 references, page 1 of 2
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 in...
Subjects
free text keywords: Letters, Molecular Medicine, Biochemistry, General Medicine, NLRP1, Programmed cell death, Inflammasome, medicine.drug, medicine, Serine, Cell biology, Chemistry, Enzyme, chemistry.chemical_classification, Proteomics, Mutant
Funded by
NIH| Weill Cornell/Rockefeller/Sloan-Kettering MST Program
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 5T32GM007739-30
  • Funding stream: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
,
NIH| MOUSE GENETICS
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 2P30CA008748-43
  • Funding stream: NATIONAL CANCER INSTITUTE
,
NIH| Characterizing the Mechanism of DPP8/9 Inhibitor-Induced Pyroptosis
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 1R01AI137168-01
  • Funding stream: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
30 references, page 1 of 2

Janeway C. A.Jr.; Medzhitov R. (2002) Innate immune recognition. Annu. Rev. Immunol. 20, 197–216. 10.1146/annurev.immunol.20.083001.084359.11861602 [OpenAIRE] [PubMed] [DOI]

Broz P.; Dixit V. M. (2016) Inflammasomes: mechanism of assembly, regulation and signalling. Nat. Rev. Immunol. 16, 407–420. 10.1038/nri.2016.58.27291964 [OpenAIRE] [PubMed] [DOI]

Lamkanfi M.; Dixit V. M. (2014) Mechanisms and functions of inflammasomes. Cell 157, 1013–1022. 10.1016/j.cell.2014.04.007.24855 941 [OpenAIRE] [PubMed] [DOI]

Martinon F.; Burns K.; Tschopp J. (2002) The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol. Cell 10, 417–426. 10.1016/S1097-2765(02)00599-3.12191486 [PubMed] [DOI]

D’Osualdo A.; Weichenberger C. X.; Wagner R. N.; Godzik A.; Wooley J.; Reed J. C. (2011) CARD8 and NLRP1 undergo autoproteolytic processing through a ZU5-like domain. PLoS One 6, e27396 10.1371/journal.pone.0027396.22087307 [OpenAIRE] [PubMed] [DOI]

Finger J. N.; Lich J. D.; Dare L. C.; Cook M. N.; Brown K. K.; Duraiswami C.; Bertin J.; Gough P. J. (2012) Autolytic proteolysis within the function to find domain (FIIND) is required for NLRP1 inflammasome activity. J. Biol. Chem. 287, 25030–25037. 10.1074/jbc.M112.378323.22665479 [OpenAIRE] [PubMed] [DOI]

Frew B. C.; Joag V. R.; Mogridge J. (2012) Proteolytic processing of Nlrp1b is required for inflammasome activity. PLoS Pathog. 8, e1002659 10.1371/journal.ppat.1002659.22536155 [OpenAIRE] [PubMed] [DOI]

Boyden E. D.; Dietrich W. F. (2006) Nalp1b controls mouse macrophage susceptibility to anthrax lethal toxin. Nat. Genet. 38, 240–244. 10.1038/ng1724.16429160 [OpenAIRE] [PubMed] [DOI]

Levinsohn J. L.; Newman Z. L.; Hellmich K. A.; Fattah R.; Getz M. A.; Liu S.; Sastalla I.; Leppla S. H.; Moayeri M. (2012) Anthrax lethal factor cleavage of Nlrp1 is required for activation of the inflammasome. PLoS Pathog. 8, e1002638 10.1371/journal.ppat.1002638.22479187 [OpenAIRE] [PubMed] [DOI]

Hellmich K. A.; Levinsohn J. L.; Fattah R.; Newman Z. L.; Maier N.; Sastalla I.; Liu S.; Leppla S. H.; Moayeri M. (2012) Anthrax lethal factor cleaves mouse nlrp1b in both toxin-sensitive and toxin-resistant macrophages. PLoS One 7, e49741 10.1371/journal.pone.0049741.23152930 [OpenAIRE] [PubMed] [DOI]

Chavarria-Smith J.; Vance R. E. (2013) Direct proteolytic cleavage of NLRP1B is necessary and sufficient for inflammasome activation by anthrax lethal factor. PLoS Pathog. 9, e1003452 10.1371/journal.ppat.1003452.23818853 [OpenAIRE] [PubMed] [DOI]

Sandstrom A.; Mitchell P. S.; Goers L.; Mu E. W.; Lesser C. F.; Vance R. E. (2019) Functional degradation: A mechanism of NLRP1 inflammasome activation by diverse pathogen enzymes. Science 364, eaau1330 10.1126/science.aau1330.30872533 [OpenAIRE] [PubMed] [DOI]

Chui A. J.; Okondo M. C.; Rao S. D.; Gai K.; Griswold A. R.; Johnson D. C.; Ball D. P.; Taabazuing C. Y.; Orth E. L.; Vittimberga B. A.; Bachovchin D. A. (2019) N-terminal degradation activates the NLRP1B inflammasome. Science 364, 82–85. 10.1126/science.aau1208.30872531 [OpenAIRE] [PubMed] [DOI]

Ewald S. E.; Chavarria-Smith J.; Boothroyd J. C. (2014) NLRP1 is an inflammasome sensor for Toxoplasma gondii. Infect. Immun. 82, 460–468. 10.1128/IAI.01170-13.24218483 [OpenAIRE] [PubMed] [DOI]

Cirelli K. M.; Gorfu G.; Hassan M. A.; Printz M.; Crown D.; Leppla S. H.; Grigg M. E.; Saeij J. P.; Moayeri M. (2014) Inflammasome sensor NLRP1 controls rat macrophage susceptibility to Toxoplasma gondii. PLoS Pathog. 10, e1003927 10.1371/journal.ppat.1003927.24626226 [OpenAIRE] [PubMed] [DOI]

30 references, page 1 of 2
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