Hollingsworth_2020_Biorxiv__

Reference

Title : DPP9 directly sequesters the NLRP1 C-terminus to repress inflammasome activation - Hollingsworth_2020_Biorxiv__
Author(s) : Hollingsworth LR , Sharif H , Griswold AR , Fontana P , Mintseris J , Dagbay KB , Paulo JA , Gygi SP , Bachovchin DA , Wu
Ref : Biorxiv , : , 2020
Abstract : NLRP1 is a cytosolic inflammasome sensor that mediates activation of caspase-1, which in turn induces cytokine maturation and pyroptotic cell death1-6. Gain-of-function NLPR1 mutations cause skin inflammatory diseases including carcinoma, keratosis, and papillomatosis7-14. NLRP1 contains a unique function-to-find domain (FIIND) that autoproteolyzes into noncovalently associated subdomains15-18. Proteasomal degradation of the autoinhibitory N-terminal fragment (NT) activates NLRP1 by releasing the inflammatory C-terminal fragment (CT)19,20. Cytosolic dipeptidyl peptidases 8 and 9 (DPP8/9) interact with NLRP1, and small-molecule DPP8/9 inhibitors activate NLRP1 by poorly characterized mechanisms11,19,21. Here, we report cryo-EM structures of the human NLRP1-DPP9 complex, alone and in complex with the DPP8/9 inhibitor Val-boroPro (VbP). Surprisingly, the NLRP1-DPP9 complex is a ternary complex comprised of DPP9, one intact FIIND of a non-degraded full-length NLRP1 (NLRP1-FL) and one NLRP1-CT freed by NT degradation. The N-terminus of the NLRP1-CT unfolds and inserts into the DPP9 active site but is not cleaved by DPP9, and this binding is disrupted by VbP. Structure-based mutagenesis reveals that the binding of NLRP1-CT to DPP9 requires NLRP1-FL and vice versa, and inflammasome activation by ectopic NLRP1-CT expression is rescued by co-expressing autoproteolysis-deficient NLRP1-FL. Collectively, these data indicate that DPP9 functions as a 'bomb-diffuser' to prevent NLRP1-CTs from inducing inflammation during homeostatic protein turnover.
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Gene_locus related to this paper: human-DPP9

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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 (2020)
DPP9 directly sequesters the NLRP1 C-terminus to repress inflammasome activation
Biorxiv :

Hollingsworth LR, Sharif H, Griswold AR, Fontana P, Mintseris J, Dagbay KB, Paulo JA, Gygi SP, Bachovchin DA, Wu (2020)
Biorxiv :