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.
Loss of DPP9 activity in humans, mice and zebrafish results in pathogenic NLRP1 overactivation.
NLRP1 knockout to the rescue The NLRP1 inflammasome is a protein complex crucial for various immune responses; thus, dysregulation of it can lead to severe immune disorders. Here, Harapas et al . looked at four children with dipeptidyl peptidase 9 (DPP9) loss-of-function mutations, showing that these patients had various immune disorders and spontaneous activation of the NLRP1 inflammasome in their isolated keratinocytes. Modeling these patients with a mouse model with a catalytically inactive DPP9 mutation, they found that neonate lethality could be rescued by also knocking out NLRP1. In a zebrafish model, knockout of asc, a molecule involved in NLRP1 inflammasome formation, also rescued the survival of dpp9 knockout zebrafish. Thus, DPP9 mutations seem to result in immune disorders due to NLRP1 inflammasome overactivation.