Transglutaminase 2 (TG2) is a versatile enzyme that acts like a biological glue, speeding up chemical reactions to form stable links between proteins. This process creates durable protein structures resistant to degradation. The enzyme operates in various locations within and outside of cells, including the heart, liver, and small intestine. It is important to distinguish this human enzyme from microbial transglutaminase, sometimes used in the food industry as “meat glue,” as they are distinct molecules.
The Normal Functions of Transglutaminase 2
In a healthy state, Transglutaminase 2 (TG2) performs several beneficial roles. One function is in wound healing, where TG2 helps stabilize the extracellular matrix—the scaffold that holds cells together. By cross-linking proteins like fibronectin, it strengthens the tissue structure to aid repair and recovery.
The enzyme is also involved in the routine maintenance of tissues. By creating strong bonds between proteins, TG2 contributes to the overall integrity and resilience of various organs. This protein cross-linking is fundamental to the structural soundness of tissues throughout the body.
TG2 also participates in apoptosis, or programmed cell death, the body’s natural process for removing old or damaged cells without inflammation. The enzyme helps by cross-linking proteins within a dying cell, ensuring its contents are securely packaged for clean removal by other cells. This containment prevents the release of materials that could provoke an immune response.
The Link to Celiac Disease
In genetically susceptible individuals, the link between Transglutaminase 2 (TG2) and celiac disease begins after ingesting gluten. A component of gluten called gliadin is not fully digested and can pass through the intestinal barrier. In the intestinal tissue, TG2 interacts with these gliadin fragments.
TG2 modifies the gliadin peptides through a chemical reaction called deamidation. This alteration makes the gliadin highly stimulating to the immune systems of people with HLA-DQ2 or HLA-DQ8 genes. The immune system then mistakenly identifies this modified gliadin as a foreign threat and mounts a response.
This immune reaction is twofold. It targets the modified gliadin peptides, but it also incorrectly identifies the TG2 enzyme itself as part of the threat. The immune system begins to produce antibodies against its own TG2, known as anti-tissue transglutaminase antibodies (anti-tTG). These antibodies are a hallmark of celiac disease and are the primary biomarker used in blood tests for diagnosis. The sustained immune attack, directed at both gliadin and TG2, ultimately leads to inflammation and damage to the lining of the small intestine.
Involvement in Other Health Conditions
Beyond its role in celiac disease, dysregulated Transglutaminase 2 (TG2) activity is implicated in other health conditions. Its involvement stems from its ability to cross-link proteins, which can contribute to pathology. In various forms of fibrosis, such as in the liver or lungs, overactive TG2 promotes the excessive accumulation and stiffening of the extracellular matrix. This leads to scarring and can impair organ function.
In cancer, tumor cells can co-opt TG2 to promote their own survival and spread. The enzyme helps cancer cells adhere more strongly, migrate, and resist chemotherapy and apoptosis. Elevated TG2 expression is linked to more aggressive tumors and poorer prognosis in certain cancers by supporting tumor growth and metastasis.
TG2 has also been connected to neurodegenerative diseases like Alzheimer’s, Huntington’s, and Parkinson’s. In these conditions, TG2 is thought to contribute to the formation of harmful protein aggregates. For example, it can cross-link proteins like amyloid-beta in Alzheimer’s or mutant huntingtin in Huntington’s, potentially stabilizing these toxic structures and causing neuronal damage.
Therapeutic Targeting of Transglutaminase 2
Because Transglutaminase 2 (TG2) is involved in several diseases, it has become a therapeutic target. Researchers are developing TG2 inhibitors, which are drugs designed to block the enzyme’s activity. The goal is to prevent the protein cross-linking and deamidation reactions that contribute to disease.
For celiac disease, TG2 inhibitors are being investigated as a therapy to protect the small intestine from accidental gluten exposure. By blocking TG2, these drugs could prevent the modification of gliadin, stopping the initial trigger of the immune response. This approach could offer a safety net for individuals on a strict gluten-free diet.
This strategy also holds promise for other conditions. In fibrosis, inhibiting TG2 could reduce tissue scarring. In certain cancers, blocking the enzyme might make tumor cells more susceptible to treatment and less likely to spread. TG2 inhibitors are currently in various stages of research and clinical trials and are not yet available as standard treatments.