Hollingsworth_2021_Nature_592_778

Reference

Title : DPP9 sequesters the C terminus of NLRP1 to repress inflammasome activation - Hollingsworth_2021_Nature_592_778
Author(s) : Hollingsworth LR , Sharif H , Griswold AR , Fontana P , Mintseris J , Dagbay KB , Paulo JA , Gygi SP , Bachovchin DA , Wu H
Ref : Nature , 592 :778 , 2021
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 pyroptosis(1-4). Gain-of-function mutations of NLRP1 cause severe inflammatory diseases of the skin(4-6). NLRP1 contains a function-to-find domain that auto-proteolyses into noncovalently associated subdomains(7-9), 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 unclear(10,12-14). 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 fragment(10) 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.
ESTHER : Hollingsworth_2021_Nature_592_778
PubMedSearch : Hollingsworth_2021_Nature_592_778
PubMedID: 33731932
Gene_locus related to this paper: human-DPP9

Related information

Gene_locus related to this paper: human-DPP9

Citations formats

Hollingsworth LR, Sharif H, Griswold AR, Fontana P, Mintseris J, Dagbay KB, Paulo JA, Gygi SP, Bachovchin DA, Wu H (2021)
DPP9 sequesters the C terminus of NLRP1 to repress inflammasome activation
Nature 592 :778

Hollingsworth LR, Sharif H, Griswold AR, Fontana P, Mintseris J, Dagbay KB, Paulo JA, Gygi SP, Bachovchin DA, Wu H (2021)
Nature 592 :778