Study Uncovers STING's Secondary Role as a Proton Channel

The signaling protein STING is a critical player in the human immune system, detecting signs of danger within cells and then activating a variety of defense mechanisms. When STING detects danger, it can turn on at least three different pathways—one leading to interferon production, one to non-canonical autophagy, and a third to formation of the inflammasome. The mechanism by which STING stimulates interferon production is well characterized, but it has not been understood how it activates the other two processes.

Previous research has shown that both autophagy and formation of inflammasomes can be provoked by protons leaking from cell organelles, which makes the inside of the cell more acidic. Because of that, a team of MIT and Harvard Medical School researchers wondered if STING might somehow induce proton leakage.

To explore this possibility, they labeled the Golgi with a protein that fluoresces when the pH goes up. When they treated the cells with a molecule that activates STING, the Golgi became less acidic, meaning that it was losing protons. A genetic screen minimized the possibility of another ion channel controlling this ion flow, so the researchers hypothesized that STING itself was acting as a proton channel.

According to the study published in Science, STING is the first human immune sensor that can translate danger signals into ion flow.   

“Because of its importance to host immunity, there is a great interest in developing drugs that can activate or suppress STING activity, and the discovery of STING’s ion channel activity will provide new ways to think about designing therapeutics to modulate STING,” explained Darrell Irvine, a senior author of the study.