Dipeptidyl peptidase 9 (DPP9) (DPP9)

Dipeptidyl peptidase 9 (DPP9) is a ubiquitous cytosolic serine protease belonging to the S9B family, characterized by its ability to cleave N-terminal dipeptides with a proline or alanine at the second position [7, 13]. It serves as a critical endogenous regulator of the innate immune system by repressing the activation of the NLRP1 and CARD8 inflammasomes through both its catalytic activity and a unique scaffolding function that sequesters their active C-terminal fragments [1, 5, 17]. Beyond its role in immunity, DPP9 is involved in the N-degron pathway, regulating the stability of proteins such as BRCA2 and adenylate kinase 2, which impacts DNA repair and cellular energy homeostasis [9, 12]. In the context of drug development, DPP9 is a significant safety target; off-target inhibition by early-generation DPP4 inhibitors was linked to severe toxicities, including skin lesions and hematological issues, in animal models [15, 18]. Conversely, selective DPP9 inhibition is being explored as a potential strategy for cancer immunotherapy to induce pyroptosis in malignant cells [6, 9]. Mutations in the DPP9 gene are associated with rare autoinflammatory syndromes and have been linked to increased susceptibility to severe COVID-19 and pulmonary fibrosis [3, 10, 17].

Other names

DPP-IXDPRP-2Dipeptidyl peptidase IV-related protein 2DPLP9DPRP2DP9Dipeptidyl peptidase-like protein 9IMD111HATIS

Competitive inhibition of the serine protease active site and disruption of the inhibitory scaffolding complex with NLRP1 and CARD8, leading to the release of active inflammasome fragments and subsequent pyroptosis [1, 5, 14].