Transglutaminase 2 (TGM2) is a highly versatile enzyme found throughout the body, playing a role in numerous biological processes. Despite its widespread presence and diverse functions, it remains largely unknown to the general public. This enzyme’s involvement spans from maintaining tissue integrity to influencing cell survival, making it a subject of increasing scientific interest.
Understanding Transglutaminase 2
Transglutaminase 2 (TGM2 or tTG) is a 78-kDa enzyme in the protein-glutamine $\gamma$-glutamyltransferases family. Its primary action is forming strong, stable bonds between proteins, a process known as transamidation or cross-linking. This creates an isopeptide bond that resists degradation.
Beyond cross-linking, TGM2 also catalyzes deamidation and GTP-binding/hydrolyzing activities. The enzyme is found in various cellular locations, including the cytosol, nucleus, cell surface, and extracellular matrix. TGM2 becomes active in the presence of calcium, which activates it by changing its shape.
Essential Functions in the Body
TGM2 contributes to several physiological roles. It helps stabilize the extracellular matrix (ECM), the network of proteins and carbohydrates surrounding cells, by cross-linking various ECM proteins. This makes the ECM stiffer and more resistant to degradation, supporting tissue integrity and repair. TGM2 also participates in cell adhesion, acting as a co-receptor for integrins, which are proteins on the cell surface that mediate cell-to-cell and cell-to-ECM interactions. This interaction promotes cell attachment and spreading.
The enzyme plays a role in programmed cell death, or apoptosis, by stabilizing the dying cell’s structure and preventing leakage of its contents. This helps maintain cellular homeostasis. TGM2 is also involved in wound healing, where its deposition in the ECM helps in tissue reconstruction and stabilization following injury. TGM2 influences immune responses, with its expression increasing on the surface of differentiating monocytes and contributing to the adhesion and migration of leukocytes during inflammation.
Connection to Health Conditions
Dysregulation or abnormal activity of TGM2 has been linked to various health conditions. In celiac disease, TGM2 is a primary autoantigen, meaning the immune system mistakenly targets it. TGM2 modifies gluten peptides through deamidation, changing glutamine residues into glutamic acid, which enhances their recognition by immune cells in genetically predisposed individuals. This modification triggers a strong immune response that damages the small intestine.
TGM2 is also implicated in neurodegenerative disorders such as Huntington’s disease, Alzheimer’s disease, and Parkinson’s disease. These conditions involve abnormal protein aggregates, and TGM2’s transamidation activity promotes their formation. For instance, TGM2 catalyzes the cross-linking of $\alpha$-synuclein, a protein involved in Parkinson’s disease, leading to the formation of insoluble aggregates.
In various types of cancer, TGM2 can act as a factor for cancer cell survival, influencing cell migration, invasion, and resistance to chemotherapy drugs. High TGM2 expression is observed in drug-resistant and metastatic tumors, promoting processes like epithelial-mesenchymal transition (EMT) that aid tumor spread. TGM2’s role in cancer cell survival can involve either its GTP-bound signaling activity or its transamidase activity, depending on the cancer type.
Additionally, TGM2 contributes to fibrotic conditions, such as liver and kidney fibrosis. In these conditions, TGM2’s transamidase activity contributes to tissue scarring by stabilizing extracellular matrix components like collagen through cross-linking. This enhanced stabilization can lead to excessive accumulation of scar tissue, impairing organ function.
Therapeutic Potential and Research
Research explores TGM2 as a therapeutic target for various diseases. Given its involvement in celiac disease, neurodegenerative disorders, cancers, and fibrotic conditions, modulating TGM2 activity is a promising treatment avenue. Scientists are developing TGM2 inhibitors to block its enzymatic activity, or activators to enhance its beneficial roles. For instance, in celiac disease, inhibiting TGM2’s ability to deamidate gluten peptides could reduce the immune response.
Studies also investigate TGM2 as a diagnostic biomarker. Elevated TGM2 levels or specific TGM2-related antibodies are observed in diseases, suggesting they could indicate diagnosis or disease progression. While research is ongoing, these investigations highlight the potential for TGM2-targeted therapies and diagnostic tools to improve patient outcomes.