Alternative titles; symbols
HGNC Approved Gene Symbol: DPP4
Cytogenetic location: 2q24.2 Genomic coordinates (GRCh38): 2:161,992,245-162,074,215 (from NCBI)
Dipeptidyl peptidase IV (DPP4; EC 3.4.14.5) is a serine exopeptidase that cleaves X-proline dipeptides from the N terminus of polypeptides. It is an intrinsic membrane glycoprotein anchored into the cell membrane by its N-terminal end. High levels of the enzyme are found in the brush-border membranes of the kidney proximal tubule and of the small intestine, but several other tissues also express the enzyme. The enzyme is present in the fetal colon but disappears at birth. It is ectopically expressed in some human colon adenocarcinomas and human colon cancer cell lines (Darmoul et al., 1990; Darmoul et al., 1992).
Daddona and Kelley (1979) noted that in many human tissues adenosine deaminase (ADA; 608958) exists as a large molecular weight complex composed of ADA and an adenosine deaminase-binding protein (ADBP), also known as adenosine deaminase complexing protein-2 (ADCP2). Data presented by Kameoka et al. (1993) and partial amino acid sequence data presented by Morrison et al. (1993) indicated that adenosine deaminase-binding protein is identical to CD26, a T-cell activation molecule and a 110-kD glycoprotein that is present also on epithelial cells of various tissues including the liver, kidney, and intestine.
Misumi et al. (1992) isolated and sequenced the cDNA coding for DPP4. The nucleotide sequence (3,465 bp) of the cDNA contained an open reading frame encoding a polypeptide comprising 766 amino acids, 1 residue less than those of the rat protein. The predicted amino acid sequence exhibited 84.9% identity to that of the rat enzyme.
Abbott et al. (1994) demonstrated that CD26 encodes 2 messages sized at about 4.2 and 2.8 kb. These are both expressed at high levels in the placenta and kidney and at moderate levels in the lung and liver. Only the 4.2 kb mRNA was expressed at low levels in skeletal muscle, heart, brain, and pancreas.
Abbott et al. (1994) demonstrated that CD26 spans approximately 70 kb and contains 26 exons, ranging in size from 45 bp to 1.4 kb. The nucleotides that encode the serine recognition site (G-W-S-Y-G) are split between 2 exons. This clearly distinguishes the genomic organization of the prolyl oligopeptidase family from that of the classic serine protease family.
From studies in mouse-man and hamster-man hybrid cells, Herbschleb-Voogt et al. (1981) concluded that a gene or genes on human chromosome 2 determine the expression of ADCP and that neither chromosome 6 nor any other of the chromosomes of man carries genes involved in the formation of ADCP.
Nguyen et al. (1981) concluded that the gene for ADCP on chromosome 2 is located between MDH1 (154200) and IDH1 (147700), i.e., in the segment 2p23-q32.
Darmoul et al. (1990) isolated a cDNA probe for intestinal dipeptidyl peptidase IV from a colon cancer cell line and, by Southern analysis of somatic cell hybrids, assigned the DDP4 gene to chromosome 2. This assignment was confirmed by Mathew et al. (1994), who sublocalized the DPP4 gene to 2q23 by fluorescence in situ hybridization.
By in situ hybridization, Darmoul et al. (1994) mapped DPP4 to chromosome 2q24. By fluorescence in situ hybridization, Abbott et al. (1994) mapped the CD26 gene to 2q24.3.
Kameoka et al. (1993) listed the reasons for thinking that ADA on the T-cell surface is regulated during the process of T-cell activation, that CD26 may be involved in regulating the extracellular concentration of ADA, and that some cases of SCID may be related to mutation in this gene.
The CD4 antigen (186940) is essential for binding human immunodeficiency virus (HIV) particles, but is not sufficient for efficient viral entry and infection. Callebaut et al. (1993) demonstrated that a cofactor necessary for efficient function is CD26. Coexpression of human CD4 and CD26 in murine NIH 3T3 cells rendered them permissive to infection by HIV. They suggested the possibility of developing specific inhibitors that would block the function of CD26 and thus be useful as effective therapeutic agents in AIDS patients.
Marguet et al. (2000) presented data indicating a critical role for CD26 in physiologic glucose homeostasis, and established it as a potential target for therapy in type II diabetes (125853). Dipeptidyl peptidase IV enzyme activity has been implicated in the regulation of the biologic activity of multiple hormones and chemokines, including the insulinotropic peptides glucagon-like peptide-1 (GLP1; 138030) and glucose-dependent insulinotropic polypeptide (GIP; 137240). Marguet et al. (2000) found that targeted inactivation of the CD26 gene yielded healthy mice that had normal blood glucose levels in the fasted state, but reduced glycemic excursion after a glucose challenge. Levels of glucose-stimulated circulating insulin and the intact insulinotropic form of GLP1 were increased in CD26 -/- mice. A pharmacologic inhibitor of DPP IV enzymatic activity improved glucose tolerance in wildtype, but not in CD26 -/-, mice. This inhibitor also improved glucose tolerance in GLP1 receptor (GLP1R; 138032) -/- mice, indicating that CD26 contributes to blood glucose regulation by controlling the activity of GLP1 as well as additional substrates.
Engel et al. (2003) studied the crystal structure of CD26 to reveal its functional regulation and enzymatic mechanism.
Dipeptidyl peptidase IV is involved in the metabolic inactivation of GLP1 and other incretin hormones. Conarello et al. (2003) studied the impact of dipeptidyl peptidase IV deficiency on body weight control and insulin sensitivity in mice. Whereas wildtype mice displayed accelerated weight gain and hyperinsulinemia when fed a high-fat diet, mice lacking the Dpp4 gene were refractory to the development of obesity (601665) and hyperinsulinemia. Pair-feeding and indirect calorimetry studies indicated that reduced food intake and increased energy expenditure accounted for the resistance to obesity in the Dpp4-null mice. Furthermore, ablation of the Dpp4 gene was associated with elevated Glp1 levels and improved metabolic control, resulting in improved insulin sensitivity, reduced pancreatic islet hypertrophy, and protection against streptozotocin-induced loss of beta cell mass and hyperglycemia. Conarello et al. (2003) concluded that dipeptidyl peptidase IV inhibition is a viable therapeutic option for the treatment of metabolic disorders related to diabetes and obesity.
Christopherson et al. (2004) presented evidence that endogenous CD26 expression on donor cells negatively regulates homing and engraftment. By inhibition or deletion of CD26, it was possible to increase greatly the efficiency of transplantation. Christopherson et al. (2004) concluded that their results suggested that hematopoietic stem cell engraftment is not absolute, as previously suggested, and indicated that improvement of bone marrow transplant efficiency may be possible in the clinic.
Ohnuma et al. (2004) demonstrated that CD26 binds to the scaffolding domain of caveolin-1 (CAV1; 601047) on antigen-presenting cells. The binding takes place by means of residues 201 to 226 of CD26, along with the serine catalytic site at position 630. On monocytes expressing tetanus toxoid (TT) antigens, the CD26-CAV1 interaction led to CAV1 phosphorylation, NFKB (see 164011) activation, and upregulation of CD86 (601020). Reduction of CAV1 expression inhibited CD26-mediated upregulation of CD86 and abrogated CD26-mediated enhancement of TT-induced T-cell proliferation. Ohnuma et al. (2004) concluded that the CD26-CAV1 interaction plays a role in CD86 upregulation on antigen-loaded monocytes and the subsequent engagement of CD86 with CD28 on T cells, leading to antigen-specific T-cell activation.
Raj et al. (2013) identified DPP4 as a functional receptor for human coronavirus-Erasmus Medical Center (hCoV-EMC), also known as Middle East respiratory syndrome coronavirus (MERS-CoV). DPP4 specifically copurified with the receptor-binding S1 domain of the hCoV-EMC spike (S) protein from lysates of susceptible Huh-7 cells. Antibodies directed against DPP4 inhibited hCoV-EMC infection of primary human bronchial epithelial cells and Huh-7 cells. The expression of human and bat (Pipistrellus pipistrellus) DPP4 in nonsusceptible COS-7 cells enabled infection by hCoV-EMC. Raj et al. (2013) concluded that the use of evolutionarily conserved DPP4 protein from different species as a functional receptor provides clues about the host range potential of hCoV-EMC.
MERS-CoV spread from an animal reservoir to infect humans in 2012, causing sporadic severe and frequently fatal respiratory disease. In individuals with comorbidities, such as diabetes or respiratory or renal disease, infection can cause widespread pneumonia, with case fatality rates of about 40%. By expressing DPP4 from humans and other animal species in primate and rodent cell lines, Barlan et al. (2014) showed that blades 4 and 5 of the 8-blade beta-propeller region of DPP4, which confer binding and susceptibility to MERS-CoV, could replace those blades in the mouse protein. The chimeric DPP4, but not wildtype mouse Dpp4, was a receptor for the virus S protein. Similar chimeric proteins using blades 4 and 5 from camels and horses, and, to a lesser extent, bats and goats, also conferred susceptibility to otherwise resistant mouse astrocytoma cells. Barlan et al. (2014) proposed that the DPP4 MERS-CoV receptor and S protein-cleaving proteases combine in various animals to offer efficient entry for the virus.
Mucosal-associated invariant T (MAIT) cells express the semi-invariant T-cell receptor (TCR) alpha chain TRAV1-2 (see 615442) and detect bacteria and fungi through the nonpolymorphic MHC-like molecule MR1 (600764). Using mycobacteria-infected antigen-presenting cells, Sharma et al. (2015) showed that bacteria-reactive MR1-restricted T cells produced IFNG (147570) and TNF (191160) and shared effector function with cytolytic effector CD8 (see 186910)-positive T cells. FACS analysis demonstrated that CD26 and CD161 (KLRB1; 602890) were associated with MAIT cells. High expression of CD26 on CD8-positive/TRAV1-2-positive cells identified bacteria-reactive MR1-restricted T cells with high sensitivity and specificity, whereas CD161 identified these cells with high specificity but low sensitivity. Cell surface expression of CD8, TRAV1-2, and CD26-high was lacking in blood of patients with active tuberculosis (see 607948), but it was restored in patients undergoing treatment.
Ghorpade et al. (2018) showed that obesity in mice stimulates hepatocytes to synthesize and secrete DPP4, which acts with plasma factor Xa (see 613872) to inflame adipose tissue macrophages. Silencing expression of DPP4 in hepatocytes suppressed inflammation of visceral adipose tissue and insulin resistance; however, a similar effect was not seen with the orally administered DPP4 inhibitor sitagliptin. Inflammation and insulin resistance were also suppressed by silencing expression of caveolin-1 (601047) or PAR2 (600933) in adipose tissue macrophages; these proteins mediate the actions of DPP4 and factor Xa, respectively. Ghorpade et al. (2018) concluded that hepatocyte DPP4 promotes visceral adipose tissue inflammation and insulin resistance in obesity, and that targeting this pathway may have metabolic benefits that are distinct from those observed with oral DPP4 inhibitors.
Crystal Structure
To delineate the molecular basis of the specific interaction between MERS-CoV S protein and CD26, Lu et al. (2013) solved crystal structures of both the free receptor-binding domain (RBD) of the MERS-CoV spike protein and its complex with CD26. Furthermore, they measured binding between the RBD and CD26 using real-time surface plasmon resonance with a dissociation constant of 16.7 nM. The viral RBD is composed of a core subdomain homologous to that of the SARS-CoV spike protein, and a unique strand-dominated external receptor-binding motif that recognizes blades IV and V of the CD26 beta-propeller. The atomic details at the interface between the 2 binding entities revealed a protein-protein contact mediated mainly by hydrophilic residues. Sequence alignment indicated, among beta-coronaviruses, a possible structural conservation for the region homologous to the MERS-CoV RBD core, but a high variation in the external receptor-binding motif region for virus-specific pathogenesis such as receptor recognition.
Zhao et al. (2014) noted that rodents are not susceptible to MERS-CoV. They used an adenovirus vector expressing human DPP4 to generate mice sensitized to infection with MERS-CoV. These mice developed pneumonia characterized by extensive inflammatory cell infiltration with virus clearance after 6 to 8 days in a type I IFN- and T cell-dependent manner. Treatment with poly(I:C) was also efficacious in this model.
Agrawal et al. (2015) developed a transgenic mouse model expressing human DPP4 that was susceptible to MERS-CoV infection, with high titers of virus detectable in brain and lung and later in other organs.
By generating knockin mice expressing human DPP4, Pascal et al. (2015) obtained a mouse model susceptible to intranasal infection with MERS-CoV. Human monoclonal antibodies binding to the MERS-CoV S protein neutralized all variants of the virus and prevented entry into target cells. The antibodies could both prevent and treat mice humanized for DPP4. Pascal et al. (2015) concluded that the model will be valuable for assessing treatments for MERS-CoV infection and disease.
Koch and Shows (1978, 1979, 1980) concluded that at least 3 genes are involved in the expression of adenosine deaminase complexing protein: ADA (608958) on chromosome 20, ADCP1 on chromosome 6, and ADCP2 on chromosome 2. The assignment of the gene designated ADCP1 on chromosome 6 was disproved (Herbschleb-Voogt et al., 1981).
Akao et al. (1988) reported that the human p250 T-cell activation antigen detected by a monoclonal antibody is a single peptide with a molecular weight of 250 kD (TP250). They classified it serologically into cluster of differentiation, CDw26. In somatic cell hybrids, concordance between the presence of human chromosome 11 and reactivity with the specific monoclonal antibody indicated that the gene is located on that chromosome. Studies with a rearranged chromosome 11 indicated that the gene is in the region 11pter-p11.2. Later work by Kameoka et al. (1993) indicated that CD26 is quite different from the 250-kD protein studied by Akao et al. (1988). Their data suggested that CD26 is identical to the previously described ADA binding protein, otherwise known as ADCP2 or DPP4.
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