A team of Yale researchers has uncovered the importance and function of a protein crucial to insulin secretion.
The researchers showed that a protein called TMEM 24 is responsible for transporting lipids and remodeling cellular plasma membranes essential to the secretion of insulin. They also found that the protein localizes in between the endoplasm reticulum — an organelle of the cell — and the cellular membrane, where it transports the lipids required for insulin secretion from the endoplasmic reticulum to the plasma membrane.
“Our protein provides the lipids that are essential for the secretion of insulin from within cells,” said Joshua Lees, a postdoctoral fellow at the Yale School of Medicine and one of the lead authors of the paper, titled “Lipid transport by TMEM24 at ER–plasma membrane contacts regulates pulsatile insulin secretion” and published in Science on Feb. 17.
The research team was inspired by a 2013 paper titled “Insulin Biosynthetic Interaction Network Component, TMEM24, Facilitates Insulin Reserve Pool Release” in the journal Cell Reports. This paper showed a relationship between TMEM24 and insulin secretion.
After reading about this, the Yale team decided to investigate the location of the protein in the cell and how exactly it was influencing insulin secretion. Lees found that this protein had a lipid transfer domain, which is a region of the protein that could potentially carry lipids. The researchers managed to characterize the protein using x-ray crystallography, a method that allowed them to determine how the structure of the protein’s lipid transfer fold came to be.
To discover where the protein localized within the cell, the researchers over-expressed the protein and found it between the endoplasmic reticulum and the cellular membrane.
Given that it had a fold associated with lipid transfer, the researchers then wanted to confirm that this protein was involved in lipid transfer. They set up another experiment in which an artificial membrane with the proteins and the lipid it transferred were present, as well as a membrane in which they were not. The membranes that previously had no protein or test lipid were found to have test lipid inside them, supporting the conclusion that these proteins were in fact transfer proteins responsible for the movement of these lipids.
The 2013 study found that when TMEM24 expression was reduced, insulin secretion was similarly diminished. However, the Yale team wondered whether the lipid-transfer function of the protein was critical in the insulin secretion process. The researchers tested this by using a gene-editing technique to express TMEM24 without the lipid transfer fold. After the proteins were expressed without the lipid transfer fold, insulin secretion was still found to be diminished, even though the rest of the protein was expressed.
When asked about any potential implications of their research, both Lees and lead author Mirko Messa, another medical school postdoctoral fellow, were hesitant to say that any direct applications could yet be made.
Messa said that while it is known that TMEM24 is related to insulin secretion, the team has no data on diabetes, adding that to talk about its applications would be speculative.
When Yale endocrinology and cell biology professor Jonathan Bogan was asked about the research’s implications for diabetes, he similarly underscored the lack of a connection.
“It is unclear if there are wider implications; they only just discovered the pathways, so people haven’t started looking for particular ways this might be involved in diabetes,” he said. “Who knows what could come of it, there certainly could be some therapeutic value to this.”
The Yale team is currently hoping to continue studying this protein in live models, according to Messa. In these models, the TMEM24 gene is turned off, allowing the researchers to further investigate the role played by this protein. Additionally, TMEM24 was found in high concentrations in the brain, where it could have a different role entirely.
Bogan also commented on the quality of the research conducted by the Yale team.
“There was a lot of work that was represented in that paper,” he said. “There’s nothing that ought to have been in that paper that wasn’t in it.”
More than 29 million Americans live with diabetes, according to the American Diabetes Association.