Details

Autor(en) / Beteiligte

• Hollingsworth, L Robert
• Sharif, Humayun
• Griswold, Andrew R
• Fontana, Pietro
• Mintseris, Julian
• Dagbay, Kevin B
• Paulo, Joao A
• Gygi, Steven P
• Bachovchin, Daniel A
• Wu, Hao

Titel

DPP9 sequesters the C terminus of NLRP1 to repress inflammasome activation

Ist Teil von

• Nature (London), 2021-04, Vol.592 (7856), p.778-783

Ort / Verlag

England: Nature Publishing Group

Erscheinungsjahr

2021

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.