N-terminal processing by dipeptidyl peptidase 9: Cut and Go!

Dipeptidyl peptidase 9 (DPP9) is an intracellular amino-dipeptidase with physiological roles in the immune system, DNA repair and mitochondria homeostasis, while its deregulation is linked to cancer progression and immune-associated defects. Through its rare ability to cleave a peptide bond following the imino-acid proline, DPP9 acts as a molecular switch that regulates key proteins, such as the tumor-suppressor BRCA2. In this review we will discuss key concepts underlying the outcomes of protein processing by DPP9, including substrate turn-over by the N-degron pathway. Additionally, we will review non-enzymatic roles and the regulation of DPP9 by discussing the interactome of this protease, which includes SUMO1, Filamin A, NLRP1 and CARD8. • Only few proteases can hydrolyze a proline (Pro) containing peptide bond. • DPP9 is an amino dipeptidyl-peptidase that removes N-terminal Xaa-Pro/Ala. • DPP9 regulates pyroptosis, DNA repair, B-cell signaling, mitochondria import and more. • Substrates include the tumor suppressor BRCA2, tyrosine kinase Syk, Adenylate kinase2. • By processing its substrates DPP9 targets these proteins to the N-degron pathway. [ABSTRACT FROM AUTHOR]