New research published in the Journal of Biological Chemistry describes a potential mechanism for preventing the symptoms of gluten intolerance or celiac disease. Individuals with the disease experience digestive distress triggered by gluten, a protein found in wheat-based foods. It is known that these digestive symptoms are a result of an overactive immune response when gluten is modified or “turned on” by transglutaminase-2 (TG2). The study identified an enzyme that inactivates TG2 which could pave the way for new celiac disease treatments.
"Currently, therapies to treat people with celiac disease are lacking. The best approach right now is just a strict adherence to a lifelong gluten-free diet," said Michael Yi, a chemical engineering graduate student at Stanford University who led the new study. "Perhaps the reason behind this is our relatively poor understanding of TG2."
TG2 is abundant in the small intestine and its disulfide bond keeps the enzyme inactive in the extracellular matrix. Previous research has identified the enzyme that activates TG2, thioredoxin-1 (TRX), by breaking bond. This new study focused on how the enzyme is turned off. Using in vitro cell culture experiments with HUVECs, the team identified the enzyme, endoplasmic reticulum (ER)–resident protein 57 (ERp57), which oxidizes TG2 rendering it inactive. In addition, experiments with siRNA-mediated knockdown HUVECs showed increased TG2 enzyme activity in the extracellular matrix.
The research team is exploring the existence of FDA-approved drugs that could target TG2s reversible disulfide bond on/off switch. Inhibiting or blocking TG2 could prove to be an effective treatment for celiac disease sufferers without requiring lifelong dietary restrictions.
Image: Transglutaminase 2 (TG2) is reversibly regulated by the protein cofactors thioredoxin and ERp57 via an allosteric disulfide redox switch. Image courtesy of Chaitan Khosla, Stanford University.