STING (short for stimulator of interferon genes) is considered one of the major factors that triggers the immune response in the context of infection, autoimmunity, and cancer. The signaling protein turns on genes involved in cell defense. Now, a team of MIT and Harvard Medical School researchers has discovered that STING can also act as an ion channel that allows protons to leak out of an organelle known as the Golgi body. This makes it the first human immune sensor that can translate danger signals into ion flow.

The findings are published in the journal Science in an article titled, “Human STING is a proton channel.”

“Proton leakage from organelles is a common signal for noncanonical light chain 3B (LC3B) lipidation and inflammasome activation, processes induced upon stimulator of interferon genes (STING) activation,” wrote the researchers. “On the basis of structural analysis, we hypothesized that human STING is a proton channel. Indeed, we found that STING activation induced a pH increase in the Golgi and that STING reconstituted in liposomes enabled transmembrane proton transport.”

“Arriving at this new idea that STING is a proton channel required connecting prior findings by other labs that either STING or proton flux could activate the inflammasome and non-canonical autophagy, which led us to hypothesize that STING initiates or mediates proton flux to trigger both downstream processes,” explained Nir Hacohen, PhD, a member of the Broad Institute of MIT and Harvard, a professor of medicine at Massachusetts General Hospital and Harvard Medical School, and a senior author of the study.

“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,” said Darrell Irvine, PhD, the Underwood-Prescott professor at MIT with appointments in the departments of biological engineering and of materials science and engineering; a member of MIT’s Koch Institute for Integrative Cancer Research and the Ragon Institute of MGH, MIT, and Harvard; and a senior author of the study.

“People know pretty well how STING induces interferon, but how STING induces autophagy and inflammasome formation has been an open debate in the field for the last 10 years,” said MIT biology PhD student Bingxu Liu.

Previous research has shown that both autophagy and formation of inflammasomes (large protein complexes that stimulate inflammation) can be provoked by protons leaking from cell organelles, which makes the inside of the cell more acidic. Because of that, the researchers wondered if STING would induce proton leakage.

The researchers 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 was acting as a proton channel.

“In addition to its biological significance, this study is a notable example of the maturing functional genomics field, where pooled screening data are sufficiently reliable to set the direction of focused investigation—even from negative results, as was the case here,” Paul Blainey, PhD, associate professor of biological engieering at MIT, said.

When the agonist C53 was added to cells, protons did not leak out of the Golgi, and downstream pathways activating autophagy and inflammasome formation were not turned on, even if STING was activated through other means.

“For the first time, we were able to decouple these downstream processes, where we can activate interferon with C53, but inhibit those other two pathways leading to autophagy and inflammasome formation,” said Rebecca Carlson PhD, a recent graduate of the Medical Engineering and Medical Physics program through the Harvard-MIT Division of Health Sciences and Technology. “In the context of inflammatory diseases where STING is overactivated, we can now start asking which of those molecular mechanisms is most important and contributes the most to the phenotype that we’re seeing.”

In future studies, the researchers hope to use C53 to determine the relative importance of these three pathways and try to figure out which ones would be most useful to stimulate or block to treat a variety of diseases.

“Now that we know that STING is an ion channel, we can propose other effects that we think could occur based on this knowledge that STING does transport protons,” Carlson added.

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