Abstract
Dipeptidyl peptidase 9 (DPP9) is a direct inhibitor of NLRP1, but how it affects inflammasome regulation in vivo is not yet established. Here, we report three families with immune-associated defects, poor growth, pancytopenia, and skin pigmentation abnormalities that segregate with biallelic DPP9 rare variants. Using patient-derived primary cells and biochemical assays, these variants were shown to behave as hypomorphic or knockout alleles that failed to repress NLRP1. The removal of a single copy of Nlrp1a/b/c, Asc, Gsdmd, or Il-1r, but not Il-18, was sufficient to rescue the lethality of Dpp9 mutant neonates in mice. Similarly, dpp9 deficiency was partially rescued by the inactivation of asc, an obligate downstream adapter of the NLRP1 inflammasome, in zebrafish. These experiments suggest that the deleterious consequences of DPP9 deficiency were mostly driven by the aberrant activation of the canonical NLRP1 inflammasome and IL-1β signaling. Collectively, our results delineate a Mendelian disorder of DPP9 deficiency driven by increased NLRP1 activity as demonstrated in patient cells and in two animal models of the disease.
| Original language | English (US) |
|---|---|
| Journal | Science immunology |
| Volume | 7 |
| Issue number | 75 |
| DOIs | |
| State | Published - Sep 16 2022 |
| Externally published | Yes |
Bibliographical note
KAUST Repository Item: Exported on 2022-12-12Acknowledgements: We thank all members of the Masters, Zhong, and Reversade laboratories for support. We thank A. Oro (Stanford University) for help in fibroblast derivation from family 1. We thank E. Kravets for study coordination and M. W. Allain for data collection (Stanford University). We thank S. Russo and E. Azzopardi for animal husbandry. We thank A. O’Donnell-Luria and S. DeTroia (Center for Mendelian Genomics at the Broad Institute of MIT and Harvard) for discussion of the genomics analysis of family 3. Funding: S.L.M. acknowledges funding from NHMRC project grants 2003159 and 2003756, the Victorian Endowment for Science, Knowledge and Innovation Fellowship, the HHMI-Wellcome International Research Scholarship, and the Sylvia and Charles Viertel Foundation Fellowship. F.L.Z. acknowledges funding from the National Research Foundation (NRF, Singapore) Fellowship. K.L. acknowledges funding from NMRC (Singapore) Open Fund–Young Individual Research Grant (OF-YIRG; MOH-000328-00). J.-L.C. acknowledges funding from the National Center for Research Resources and the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH) Clinical and Translational Science Awards (CTSA) Program (UL1TR001866), the French National Research Agency (ANR) under the “Investments for the Future” ANR program (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), the “PNEUMOPID” project (grant ANR 14-CE15-0009-01), the French Foundation for Medical Research (FRM) (EQU201903007798), the Howard Hughes Medical Institute, the Rockefeller University, the St. Giles Foundation, the Institut National de la Santé et de la Recherche Médicale (INSERM), and the Université de Paris. S.D. acknowledges funding from the Australian National Health and Medical Research Council (NHMRC) grants GNT1143412 and GNT2003756. C.-H.Y. acknowledges funding from the Walter and Eliza Hall Institute of Medical Research (WEHI) Centenary Fellowship and Ormond College’s Thwaites Gutch Fellowship in Physiology. J.G. acknowledges funding from the NIH (A.S. and M.D.F.) and NIH (grant R01HG009141) DAAD Care-For-Rare Fellowship. B.R. acknowledges funding from NRF (Singapore) Investigatorship, the Branco Weiss Foundation (Switzerland) Fellowship, the European Molecular Biology Organization (EMBO) Young Investigatorship, and the Agency for Science, Technology and Research (A*STAR, Singapore): Use-Inspired Basic Research (UIBR) Fund and A*STAR Investigatorship.