Journal article
Human DPP9 represses NLRP1 inflammasome and protects against autoinflammatory diseases via both peptidase activity and FIIND domain binding
FL Zhong, K Robinson, DET Teo, KY Tan, C Lim, CR Harapas, CH Yu, WH Xie, RM Sobota, VB Au, R Hopkins, A D’Osualdo, JC Reed, JE Connolly, SL Masters, B Reversade
Journal of Biological Chemistry | AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC | Published : 2018
Abstract
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 speci..
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Awarded by National Health and Medical Research Council
Funding Acknowledgements
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.Fellow of the Branco Weiss Foundation. Recipient of the A*STAR Investigatorship and Senior National Research Foundation (NRF) fellowship. EMBO Young Investigator.