CD26, also identified as Dipeptidyl Peptidase 4 (DPP4), is a protein found on the surface of cells throughout the body. This molecule plays a role in numerous biological processes. Its presence on diverse cell types, from immune cells to those lining organs like the kidney and intestine, highlights its broad involvement.
What is CD26?
CD26 is a glycoprotein, a protein with attached sugar chains, and it is also known as Dipeptidyl Peptidase 4 (DPP4). This protein typically resides on the outer surface of many cell types, including immune cells, fibroblasts, and epithelial cells lining organs such as the kidney, liver, and intestine. Beyond its membrane-bound form, CD26 can also exist in a soluble state, circulating freely in the blood and other bodily fluids. This protein functions as an enzyme.
How CD26 Functions
CD26 primarily functions as a serine exopeptidase, an enzyme that cleaves specific protein fragments. It removes dipeptides, small chains of two amino acids, from the N-terminus of other polypeptides. This enzymatic action is particularly specific, targeting peptides that have either proline or alanine as their second amino acid. By doing so, CD26 can modify or inactivate a wide range of bioactive molecules, including certain hormones, growth factors, and signaling molecules.
Beyond its enzymatic capabilities, CD26 also performs non-enzymatic functions. It acts as a co-receptor, interacting with various other proteins on the cell surface. For example, CD26 can associate with adenosine deaminase (ADA) and the protein tyrosine phosphatase CD45, both of which are involved in cell signaling pathways. It also participates in cell adhesion by binding to components of the extracellular matrix, such as fibronectin and collagen. These diverse interactions enable CD26 to influence a wide array of cellular processes.
CD26’s Physiological Roles
CD26 has a significant role in the immune system, particularly in the function and regulation of T cells. It is expressed on a subset of T cells, notably CD4+ helper/memory cells, and its expression levels increase upon T-cell activation. CD26 can deliver co-stimulatory signals that enhance T-cell activation, promoting their proliferation and influencing their differentiation. It also contributes to lymphocyte function by affecting cell migration and modulating chemokine signals.
In metabolic regulation, CD26 plays a role in glucose homeostasis. It is responsible for the degradation of incretin hormones, such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). These hormones are released after meals and stimulate insulin secretion from the pancreas, thereby lowering blood glucose levels. By cleaving and inactivating GLP-1 and GIP, CD26 helps regulate the duration of their action.
CD26 also has implications in tissue regeneration. Studies indicate that CD26-positive fibroblasts are involved in collagen production during wound healing in human skin. These cells contribute significantly to the formation of new collagen, a process essential for tissue repair and structural integrity.
CD26 and Human Disease
CD26 is closely linked to Type 2 Diabetes. In this condition, CD26’s enzymatic activity rapidly degrades incretin hormones like GLP-1 and GIP, which are essential for stimulating insulin release after meals. Higher levels of CD26 expression on T cells and in the circulation have been observed in individuals with Type 2 Diabetes. This increased activity contributes to the impaired glucose control seen in the disease.
The role of CD26 in cancer is complex and can vary depending on the cancer type. It can act as either a tumor suppressor or a promoter of cancer progression. In some cancers, a decrease in CD26 expression is associated with disease progression, while in others, its presence may promote invasiveness and metastasis. Altered levels of CD26, whether on cell surfaces or in the serum, can serve as markers for various cancers.
CD26 has also been identified as a receptor for certain viral infections. For instance, the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) has been shown to bind to DPP4/CD26 to gain entry into human cells. This interaction occurs on cells in the airways and kidneys, areas where the virus causes infection.
CD26 as a Therapeutic Target
The understanding of CD26’s role in glucose metabolism has led to the development of a class of medications called DPP4 inhibitors, or gliptins. These oral hypoglycemic drugs manage Type 2 Diabetes. By blocking the activity of the CD26 enzyme, these inhibitors prevent the rapid breakdown of GLP-1 and GIP, thereby prolonging their beneficial effects on insulin secretion and blood glucose regulation.
Examples of DPP4 inhibitors include sitagliptin, saxagliptin, and linagliptin. These medications help lower blood sugar levels, primarily after meals, without causing hypoglycemia. Beyond diabetes, CD26 is also being explored as a therapeutic target in other conditions. Research is ongoing into its involvement in certain cancers and autoimmune conditions, suggesting future medical interventions.