Amazing Role of Immune Regulator Revealed

STING, a signaling protein, is an important actor in the human immune regulator, recognizing danger within cells and activating a number of defense mechanisms.

STING is primarily looking for DNA, which can signify a foreign intruder like a virus or damage to the host tissue or cell. When STING detects a danger signal, it can activate at least three different pathways: one that leads to interferon production, another that leads to non-canonical autophagy (which is involved in recycling cell components and clearing pathogens), and a third that leads to the formation of the inflammasome, a protein complex that activates inflammatory responses.

The method by which STING increases interferon production is well recognized, but how it triggers the other two processes is not. STING activates those two pathways, according to a team of MIT and Harvard Medical School researchers. They discovered that STING has a hitherto unknown function: it can behave as an ion channel, allowing protons to seep out of an organelle known as the Golgi body. As a result, it is the first human immunological sensor capable of translating danger signals into ion flow.

“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,” says Nir Hacohen, 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,” says Darrell Irvine, 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. Earlier study from the Northwestern Medicine Researchers revealed a novel mechanism that regulates immune cell recruitment into tissues during inflammation.

The paper’s principal authors are MIT biology Ph.D. student Bingxu Liu and Rebecca Carlson Ph.D., a recent graduate of the Medical Engineering and Medical Physics program under the Harvard-MIT Division of Health Sciences and Technology. The paper is also co-authored by Paul Blainey, the Karl Van Tassel Associate Professor of Biological Engineering at MIT and a member of the Broad Institute and the Koch Institute.

A surprise part

STING (short for stimulator of interferon genes) is regarded as one of the most important factors that initiates the immune response in the setting of infection, autoimmunity, and cancer. STING-activating medicines have been created and tested in clinical trials as cancer immunotherapy medications to encourage the immune system to attack tumors.

STING is a membrane-spanning protein that is typically found embedded in the membrane of an organelle termed the endoplasmic reticulum (ER). When it finds DNA, it moves to the Golgi body and starts activating proteins that switch on genes essential for interferon production.

“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,” Liu says.

Previous study has shown that protons leaking from cell organelles, which causes the inside of the cell to become more acidic, can trigger both autophagy and the creation of inflammasomes (large protein complexes that stimulate inflammation). As a result, the researchers pondered if STING could trigger proton leaking.

To investigate this hypothesis, the scientists tagged the Golgi with a protein that fluoresces when the pH rises. When scientists exposed the cells to a chemical that stimulates STING, the Golgi became less acidic, indicating that protons were being lost. The researchers hypothesized that STING was working as a proton channel after a genetic test eliminated the likelihood of another ion channel directing this ion flow.

“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,” Blainey says.

After running the STING protein structure through a computer model that predicts if a given protein structure contains a pore, the researchers discovered that the STING protein is anticipated to possess a pore-like area. Surprisingly, a firm looking for STING agonists (molecules that activate STING) discovered a novel molecule last year that was later demonstrated by an academic group to bind in this same position.

The MIT/Harvard researchers believed that the agonist, known as C53, would block the putative pore. Protons did not leak out of the Golgi when C53 was given to cells, and downstream pathways promoting autophagy and inflammasome production were not activated, even when STING was activated in other ways. However, interferon activation, which occurs via a separate mechanism, continued to occur.

“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,” Carlson says. “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.”

Control by selection

The researchers intend to employ C53 in future experiments to assess the relative relevance of these three pathways and to determine which ones would be most effective to activate or block in order to cure a range of disorders.

Despite the fact that several clinical trials are now underway, the US Food and Drug Administration has not approved any STING agonists. One possible reason why other STING agonists have not progressed beyond clinical trials is that the medication can cause undesired cell death mediated by STING. According to the MIT/Harvard researchers, drugs that boost interferon production but not cell death or other inflammatory pathways could help overcome this barrier.

The researchers hope to explore whether STING might play a role in influencing the behavior of other cellular activities known to be controlled by ion channels. “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 says.

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