Advances in Understanding the Expression and Function of Dipeptidyl Peptidase 8 and 9

Abstract

DPP8 and DPP9 are recently identified members of the dipeptidyl peptidase IV (DPPIV) enzyme family, which is characterized by the rare ability to cleave a post-proline bond two residues from the N-terminus of a substrate. DPP8 and DPP9 have unique cellular localization patterns, are ubiquitously expressed in tissues and cell lines, and evidence suggests important contributions to various biological processes including: cell behavior, cancer biology, disease pathogenesis, and immune responses. Importantly, functional differences between these two proteins have emerged, such as DPP8 may be more associated with gut inflammation whereas DPP9 is involved in antigen presentation and intracellular signaling. Similarly, the DPP9 connections with H-Ras and SUMO1, and its role in AKT1 pathway downregulation provide essential insights into the molecular mechanisms of DPP9 action. The recent discovery of novel natural substrates of DPP8 and DPP9 highlights the potential role of these proteases in energy metabolism and homeostasis. This review focuses on the recent progress made with these post-proline dipeptidyl peptidases and underscores their emerging importance.

Unravelling the immunological roles of dipeptidyl peptidase 4 (DPP4) activity and/or structure homologue (DASH) proteins

“…Furthermore, DPP9 was also shown to cleave enzymatically an as-yet unknown substrate involved in the phosphorylation of protein kinase B (Akt), thereby interfering with epidermal growth factor (EGF) signalling [41]. Its binding to Harvey rat sarcoma viral oncogene homologue (H-RAS) and small ubiquitin-like modifier (SUMO)1 also confirmed the involvement of DPP9 in signal transduction [42]. Recent systematic degradomic analysis and two-dimensional difference gel electrophoresis (2D DIGE) identified several substrates involved in antigen presentation, signal transduction, cellular energy and nucleotide metabolism [34,40].…”

“…Using several chromogenic substrates, DPP9 exhibited DPP4-like activity similar to DPP4, and was shown to truncate NPY, GLP-1, GLP2 and, to a far lesser extent, for PYY in vitro [6,12,31]. However, the cytoplasmic proteasome-derived antigenic peptide RU1 [34][35][36][37][38][39][40][41][42] , CXCL10, IL-1RA, S100-A10, SET nuclear proto-oncogene (SET) and human nucleobindin 1 (NUCB1) could be identified as natural substrates of DPP9, suggesting DPP9 to play an important role in peptide turnover and antigen presentation and inflammation [39,40]. Intriguingly, DPP9 was only able to hydrolyse the deglycosylated IL-1RA isoform.…”

Sitagliptin for Type 2 diabetes: a 2015 update

“…Sitagliptin is selective for DPP-4 and in vitro does not inhibit the activity of related peptidases, DPP-8 or DPP-9, at concentrations close to therapeutic doses. While the clinical importance of this selectivity is not known, evidence suggests that DDP-8 and DPP-9 are involved in cancer biology, disease pathogenesis and immune responses [14].…”

The amino terminus extension in the long dipeptidyl peptidase 9 isoform contains a nuclear localization signal targeting the active peptidase to the nucleus

“…Members of the S9B/DPPIV family are serine amino peptidases with the unique ability to cleave off N-terminal dipeptides from proteins/peptides having a proline residue at position 2 (X aa P). Four active members of this family are known so far: the two membrane-bound cell-surface members dipeptidyl peptidase IV (DPPIV) and the Fibroblast activation protein alpha (FaP), as well as the two soluble members DPP8 and 1 3 DPP9 (reviewed in [3][4][5][6]). Dimerization is a common feature for members of the S9B/DPPIV family [6][7][8][9][10][11] and is essential for enzymatic activity [12][13][14][15][16].…”