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TitleDPP9 sequesters the C terminus of NLRP1 to repress inflammasome activation.
Journal, issue, pagesNature, Vol. 592, Issue 7856, Page 778-783, Year 2021
Publish dateMar 17, 2021
AuthorsL Robert Hollingsworth / Humayun Sharif / Andrew R Griswold / Pietro Fontana / Julian Mintseris / Kevin B Dagbay / Joao A Paulo / Steven P Gygi / Daniel A Bachovchin / Hao Wu /
PubMed AbstractNucleotide-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 ...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 pyroptosis. Gain-of-function mutations of NLRP1 cause severe inflammatory diseases of the skin. NLRP1 contains a function-to-find domain that auto-proteolyses into noncovalently associated subdomains, and proteasomal degradation of the repressive N-terminal fragment of NLRP1 releases its inflammatory C-terminal fragment (NLRP1 CT). 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 unclear. 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 fragment 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.
External linksNature / PubMed:33731932 / PubMed Central
MethodsEM (single particle)
Resolution2.9 - 3.6 Å
Structure data

22074

6x6a

EMDB-22074, PDB-6x6a:
Cryo-EM structure of NLRP1-DPP9 complex
Method: EM (single particle) / Resolution: 3.6 Å

22075

6x6c

EMDB-22075, PDB-6x6c:
Cryo-EM structure of NLRP1-DPP9-VbP complex
Method: EM (single particle) / Resolution: 2.9 Å

Chemicals

ChemComp-GK2:
[(2~{R})-1-[(2~{R})-2-azanyl-3-methyl-butanoyl]pyrrolidin-2-yl]boronic acid

Source
  • homo sapiens (human)
KeywordsIMMUNE SYSTEM / NLRP1 / DPP9 / inflammasome / Val-boroPro (VbP) / talabostat / innate immunity

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