Journal
SCIENCE IMMUNOLOGY
Volume 7, Issue 75, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciimmunol.abi4611
Keywords
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Categories
Funding
- NHMRC [2003159, 2003756]
- Victorian Endowment for Science, Knowledge and Innovation Fellowship
- HHMI-Wellcome International Research Scholarship
- Sylvia and Charles Viertel Foundation Fellowship
- National Research Foundation (NRF, Singapore) Fellowship
- NMRC (Singapore) Open Fund-Young Individual Research Grant (OF-YIRG) [MOH-000328-00]
- National Center for Research Resources of the National Institutes of Health (NIH) Clinical and Translational Science Awards (CTSA) Program [UL1TR001866]
- National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH) Clinical and Translational Science Awards (CTSA) Program [UL1TR001866]
- French National Research Agency (ANR) under the Investments for the Future ANR program [ANR-10-IAHU-01]
- French Foundation for Medical Research (FRM) [EQU201903007798]
- Howard Hughes Medical Institute
- Rockefeller University
- St. Giles Foundation
- Institut National de la Sante et de la Recherche Medicale (INSERM)
- Universite de Paris
- Australian National Health and Medical Research Council (NHMRC) [GNT1143412, GNT2003756]
- Walter and Eliza Hall Institute of Medical Research (WEHI) Centenary Fellowship
- NIH DAAD Care-For-Rare Fellowship [R01HG009141]
- NRF (Singapore)
- Branco Weiss Foundation (Switzerland) Fellowship
- European Molecular Biology Organization (EMBO) Young Investigatorship
- Agency for Science, Technology and Research (A*STAR, Singapore)
- Ormond College's Thwaites Gutch Fellowship in Physiology
- NIH
- Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence [ANR-10LABX-62-IBEID]
- PNEUMOPID project [ANR 14-CE15-0009-01]
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In this study, we report that DPP9 deficiency is associated with immune-related defects and other symptoms, and provide evidence that these defects are mainly caused by abnormal activation of the NLRP1 inflammasome and IL-1 ss signaling. This study highlights DPP9 deficiency as a Mendelian genetic disorder.
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-1 ss 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.
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