While gluten-free foods seem like a food trend to some, for others they are a medical necessity. Gluten triggers symptoms in people with celiac disease, an autoimmune disorder impacting around one in 100 people. In those with the disorder, gluten causes an overactive immune response after being modified in the small intestine by an enzyme called TG2, transglutaminase 2. Reporting in the Journal of Biological Chemistry, the researchers have discovered another enzyme that can inactivate TG2, and may help create celiac disease therapeutics.
"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," explained the study leader, Michael Yi, a chemical engineering graduate student at Stanford University. "Perhaps the reason behind this is our relatively poor understanding of TG2."
While it’s well known that gluten and TG2 interact to cause an immune response, and their interaction has been investigated, there are unanswered questions, like what TG2 does in the intestines of healthy people.
The director of Stanford Chemistry, Engineering & Medicine for Human Health, Professor Chaitan Khosla, oversaw the new work and has already led several studies indicating that TG2 is either active or inactive, depending on whether a disulfide bond in the enzyme is formed or broken.
"Though there's a lot of transglutaminase 2 protein in the (small intestine), it's all inactive," Khosla explained. "When it became clear that even though the protein was abundant, its activity was nonexistent in a healthy organ, the question became 'What turns the protein on, and then what turns the protein off?'" Several years ago, Khosla's team found the enzyme that breaks the disulfide bond, activating TG2. Now, the researchers conducted experiments that identified the enzyme that recreates that bond and turns off TG2 - ERp57. That enzyme has been understood to help fold cellular proteins inside of cells. But when it inactivates TG2, it functions outside of cells, raising other questions.
"Nobody really understands how (Erp57) gets outside the cell," Khosla noted. "The general thinking is that it's exported from the cell in small quantities; this particular observation suggests that it actually does have a biological role outside the cell."
Now, TG2 is the first protein we know of with a reversible disulfide bond that acts as an on/off switch. "This is a very different kind of on-and-off chemistry than the kind that medicinal chemists would (typically) use," Khosla explained.
Now the team is building on their findings; they want to know if any FDA approved drugs already exist that can act on this switch. Previous work has suggested that low levels of TG2 don’t harm mice. Stopping TG2 may be a way to treat those with celiac disease, so they don’t have to follow a restrictive diet forever.