DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling

Cassandra R. Harapas, Kim S. Robinson, Kenneth Lay, Jasmine Wong, Ricardo Moreno Traspas, Nasrin Nabavizadeh, Annick Rass-Rothschild, Bertrand Boisson, Scott B. Drutman, Pawat Laohamonthonkul, Devon Bonner, Jingwei Rachel Xiong, Mark D. Gorrell, Sophia Davidson, Chien-Hsiung Yu, Mark D. Fleming, Jonas Gudera, Jerry Stein, Miriam Ben-Harosh, Emily GroopmanAkiko Shimamura, Hannah Tamary, Hulya Kayserili, Nevin Hatipoğlu, Jean-Laurent Casanova, Jonathan A. Bernstein, Franklin L. Zhong, Seth L. Masters

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

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 languageEnglish (US)
JournalScience immunology
Volume7
Issue number75
DOIs
StatePublished - Sep 16 2022
Externally publishedYes

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