DPP9 sequesters the C terminus of NLRP1 to repress inflammasome activation Journal Article

   

Authors:	Hollingsworth, L. R.; Sharif, H.; Griswold, A. R.; Fontana, P.; Mintseris, J.; Dagbay, K. B.; Paulo, J. A.; Gygi, S. P.; Bachovchin, D. A.; Wu, H.
Article Title:	DPP9 sequesters the C terminus of NLRP1 to repress inflammasome activation
Abstract:	Nucleotide-binding domain and leucine-rich repeat pyrin-domain containing protein 1 (NLRP1) is an inflammasome sensor that mediates the activation of caspase-1 to induce cytokine maturation and pyroptosis1–4. Gain-of-function mutations of NLRP1 cause severe inflammatory diseases of the skin4–6. NLRP1 contains a function-to-find domain that auto-proteolyses into noncovalently associated subdomains7–9, and proteasomal degradation of the repressive N-terminal fragment of NLRP1 releases its inflammatory C-terminal fragment (NLRP1 CT)10,11. Cytosolic dipeptidyl peptidases 8 and 9 (hereafter, DPP8/DPP9) both interact with NLRP1, and small-molecule inhibitors of DPP8/DPP9 activate NLRP1 by mechanisms that are currently unclear10,12–14. Here we report cryo-electron microscopy structures of the human NLRP1–DPP9 complex alone and with Val-boroPro (VbP), an inhibitor of DPP8/DPP9. The structures reveal a ternary complex that comprises DPP9, full-length NLRP1 and the NLRPT CT. The binding of the NLRP1 CT to DPP9 requires full-length NLRP1, which suggests that NLRP1 activation is regulated by the ratio of NLRP1 CT to full-length NLRP1. Activation of the inflammasome by ectopic expression of the NLRP1 CT is consistently rescued by co-expression of autoproteolysis-deficient full-length NLRP1. The N terminus of the NLRP1 CT inserts into the DPP9 active site, and VbP disrupts this interaction. Thus, VbP weakens the NLRP1–DPP9 interaction and accelerates degradation of the N-terminal fragment10 to induce inflammasome activation. Overall, these data demonstrate that DPP9 quenches low levels of NLRP1 CT and thus serves as a checkpoint for activation of the NLRP1 inflammasome. © 2021, The Author(s), under exclusive licence to Springer Nature Limited part of Springer Nature.
Keywords:	gene expression; protein; enzyme activity; inhibitor; enzyme; inhibition; sensor; chemical composition; chemical compound; induced response
Journal Title:	Nature
Volume:	592
Issue:	7856
ISSN:	0028-0836
Publisher:	Nature Publishing Group
Date Published:	2021-04-29
Start Page:	778
End Page:	783
Language:	English
DOI:	10.1038/s41586-021-03350-4
PUBMED:	33731932
PROVIDER:	scopus
PMCID:	PMC8299537
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85103028237&doi=10.1038%2fs41586-021-03350-4&partnerID=40&md5=cfe976624247f2b3e1c0ffdc0d05a99f
Notes:	Article -- Export Date: 1 June 2021 -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/181402