Journal News

JBC: Seeking an off switch
for celiac disease

Researchers at Stanford have discovered how a disease-associated protein gets inactivated, opening the door to possible new treatments
Sasha Mushegian
Dec. 1, 2018

Celiac disease is an autoimmune disorder that affects, by some estimates, nearly one in 100 people. Celiac symptoms ar triggered by gluten, a protein found in wheat and related plants, but gluten doesn’t act alone to cause the digestive problems that patients suffer. Rather, gluten induces an overactive immune response when it’s modified by the enzyme transglutaminase 2, or TG2, in the small intestine.

Research published in the Journal of Biological Chemistry identifies an enzyme that turns off TG2, potentially paving the way for new treatments for celiac disease. Michael Yi, a chemical engineering graduate student at Stanford University, led the study.

“Currently, therapies to treat people with celiac disease are lacking,” Yi said. “The best approach right now is just a strict adherence to a lifelong gluten-free diet. Perhaps the reason behind this is our relatively poor understanding of TG2.”

The biochemistry of how TG2 interacts with gluten and induces an immune response has been well studied, but more basic mysteries remain, such as how TG2 behaves in people without celiac disease. Chaitan Khosla, the Stanford professor and director of Stanford Chemistry, Engineering & Medicine for Human Health, who oversaw the new study, has done research showing that TG2 can be active or inactive, depending on the forming or breaking of a specific chemical bond, called a disulfide bond, between two amino acids in the enzyme.

“Even though there’s a lot of transglutaminase 2 protein in the (small intestine), it’s all inactive,” Khosla said. “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?’”

In 2011, Khosla’s team identified the enzyme that activates TG2 by breaking its disulfide bond. In the new paper, the researchers did experiments in cell cultures and found an enzyme that re-forms this bond, inactivating TG2. This enzyme, ERp57, is known mainly for helping fold proteins inside the cell. When it turns off TG2, it does so outside of cells, raising more questions about its functions in healthy people.

“Nobody really understands how (Erp57) gets outside the cell,” Khosla said. “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.”

TG2 is now the first protein known to have a reversible disulfide bond on/off switch of this type.

“This is a very different kind of on-and-off chemistry than the kind that medicinal chemists would (typically) use,” Khosla said.

Understanding this mechanism has led the team to investigate whether any drugs approved by the Food and Drug Administration could target the switch directly. Because previous studies have suggested that lack of TG2 doesn’t seem to affect the health of mice negatively, blocking TG2 is a promising avenue for treating celiac disease patients without requiring lifelong dietary changes.

Enjoy reading ASBMB Today?

Become a member to receive the print edition four times a year and the digital edition weekly.

Learn more
Sasha Mushegian

Sasha Mushegian is a postdoctoral fellow at Georgetown University. Follow her on Twitter.

Get the latest from ASBMB Today

Enter your email address, and we’ll send you a weekly email with recent articles, interviews and more.

Latest in Science

Science highlights or most popular articles

Gene-mutation pathway discovery paves way for targeted blood cancers therapies
News

Gene-mutation pathway discovery paves way for targeted blood cancers therapies

Nov. 3, 2024

A new study by researchers at the universities of Texas and Chicago explains the enzymatic activity that’s needed for tumor suppression in leukemias and other cancers.

Candy binges can overload your gut microbiome
News

Candy binges can overload your gut microbiome

Nov. 2, 2024

While most Halloween candies contain lots of sugar, some are better for your gut microbiome than others.

Water rescues the enzyme
Essay

Water rescues the enzyme

Oct. 31, 2024

“Sometimes you must bend the rules to get what you want.” In the case of using water in the purification of calpain-2, it was worth the risk.

Virtual issue celebrates water in ASBMB journals
Journal News

Virtual issue celebrates water in ASBMB journals

Oct. 30, 2024

Read a dozen gold open-access articles covering exciting research about the society’s 2024 Molecule of the year.

There are worse things in the water than E. coli
News

There are worse things in the water than E. coli

Oct. 29, 2024

E. coli levels determined whether Olympic swimmers could dive into the Seine this past summer. But are these bacteria the best proxy for water contamination?

Biobots arise from the cells of dead organisms
News

Biobots arise from the cells of dead organisms

Oct. 27, 2024

Given the right conditions, certain types of cells are able to self-assemble into new lifeforms after the organism they were once part of has died.