PT - JOURNAL ARTICLE AU - Franklin L. Zhong AU - Kim Robinson AU - Chrissie Lim AU - Cassandra R. Harapas AU - Chien-Hsiung Yu AU - William Xie AU - Radoslaw M. Sobota AU - Veonice Bijin Au AU - Richard Hopkins AU - John E. Connolly AU - Seth Masters AU - Bruno Reversade TI - DPP9 is an endogenous and direct inhibitor of the NLRP1 inflammasome that guards against human auto-inflammatory diseases AID - 10.1101/260919 DP - 2018 Jan 01 TA - bioRxiv PG - 260919 4099 - http://biorxiv.org/content/early/2018/02/07/260919.short 4100 - http://biorxiv.org/content/early/2018/02/07/260919.full AB - The inflammasome is a critical immune complex that activates IL-1 driven inflammation in response to pathogen- and danger-associated signals. Nod-like receptor protein-1 (NLRP1) is a widely expressed inflammasome sensor. Inherited gain-of-function mutations in NLRP1 cause a spectrum of human Mendelian diseases, including systemic autoimmunity and skin cancer susceptibility. However, its endogenous regulation and its cognate ligands are still unknown. Here we apply a proteomics screen to identify dipeptidyl dipeptidase, DPP9 as a novel interacting partner and a specific endogenous inhibitor of NLRP1 inflammasome in diverse primary cell types from human and mice. DPP9 inhibition via small molecule drugs, targeted mutations in its catalytic site and CRISPR/Cas9-mediated genetic deletion potently and specifically activate the NLRP1 inflammasome leading to pyroptosis and IL-1 processing via ASC and caspase-1. Mechanistically, DPP9 maintains NLRP1 in its monomeric, inactive state by binding to the auto-cleaving FIIND domain. NLRP1-FIIND is a self-sufficient DPP9 binding module and its disruption by a single missense mutation abrogates DPP9 binding and explains the aberrant inflammasome activation in NAIAD patients with arthritis and dyskeratosis. These findings uncover a unique peptidase enzyme-based mechanism of inflammasome regulation, and suggest that the DPP9-NLRP1 complex could be broadly involved in human inflammatory disorders.