Journal of Biological Chemistry
Volume 293, Issue 49, 7 December 2018, Pages 18864-18878
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Immunology
Human DPP9 represses NLRP1 inflammasome and protects against autoinflammatory diseases via both peptidase activity and FIIND domain binding

https://doi.org/10.1074/jbc.RA118.004350Get rights and content
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The inflammasome is a critical molecular complex that activates interleukin-1 driven inflammation in response to pathogen- and danger-associated signals. Germline mutations in the inflammasome sensor NLRP1 cause Mendelian systemic autoimmunity and skin cancer susceptibility, but its endogenous regulation remains less understood. Here we use a proteomics screen to uncover dipeptidyl dipeptidase DPP9 as a novel interacting partner with human NLRP1 and a related inflammasome regulator, CARD8. DPP9 functions as an endogenous inhibitor of NLRP1 inflammasome in diverse primary cell types from human and mice. DPP8/9 inhibition via small molecule drugs and CRISPR/Cas9-mediated genetic deletion specifically activate the human NLRP1 inflammasome, leading to ASC speck formation, pyroptotic cell death, and secretion of cleaved interleukin-1β. Mechanistically, DPP9 interacts with a unique autoproteolytic domain (Function to Find Domain (FIIND)) found in NLRP1 and CARD8. This scaffolding function of DPP9 and its catalytic activity act synergistically to maintain NLRP1 in its inactive state and repress downstream inflammasome activation. We further identified a single patient-derived germline missense mutation in the NLRP1 FIIND domain that abrogates DPP9 binding, leading to inflammasome hyperactivation seen in the Mendelian autoinflammatory disease Autoinflammation with Arthritis and Dyskeratosis. These results unite recent findings on the regulation of murine Nlrp1b by Dpp8/9 and uncover a new regulatory mechanism for the NLRP1 inflammasome in primary human cells. Our results further suggest that DPP9 could be a multifunctional inflammasome regulator involved in human autoinflammatory diseases.

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This work was supported by core funding from the Institute of Molecular and Cell Biology (IMCB) and Institute of Medical Biology (IMB) Strategic Positioning Fund (Biomedical Research Council (BMRC), A*STAR) (to B. R. and R. M. S.), Young Investigator Grant YIG 2015 (BMRC, A*STAR) (to B. R. and R. M. S.), National Medical Research Council MS-CETSA platform Grant MOHIAFCAT2/004/2015 (to B. R. and R. M. S.), National Medical Research Council Young Investigator Grant NMRC/OFYIRG/0046/2017 (to F. L. Z.), National Health and Medical Research Council Grants 1142354 and 1099262 (to S. L. M.), funds from the Sylvia and Charles Viertel Foundation (to S. L. M.), a Howard Hughes Medical Institute–Wellcome International Research Scholarship (to S. L. M.), and funds from GlaxoSmithKline (to S. L. M.). The authors declare that they have no conflicts of interest with the contents of this article.

This article contains Videos S1–S3, Figs. S1–S4, and Excel Files S1 and S2.

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The abbreviations used are:

    PYD

    pyrin domain

    IL

    interleukin

    AIADK

    autoinflammation with arthritis and dyskeratosis

    a.a.

    amino acid(s)

    IP

    immunoprecipitation

    MSPC

    multiple self-healing palmoplantar carcinoma

    DKO

    double-knockout

    PBMC

    peripheral blood mononuclear cells

    FBS

    fetal bovine serum

    TRITC

    tetramethylrhodamine isothiocyanate

    ANOVA

    analysis of variance

    OMIM

    Online Mendelian Inheritance in Man

    PI

    propidium iodide.