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Study finds a surprising new role for a major immune regulator

In addition to turning on genes involved in cell defense, the STING protein also acts as an ion channel, allowing it to control a wide variety of immune responses.

A recent study conducted by researchers from MIT and Harvard Medical School has revealed a new function of a signaling protein called STING in the human immune system. STING is responsible for detecting DNA, which can indicate the presence of foreign invaders or damage to host tissue or cells. When STING detects these danger signals, it activates various defense mechanisms, including interferon production, non-canonical autophagy, and the formation of the inflammasome. While the mechanism behind STING’s stimulation of interferon production is well understood, how it activates the other two processes has remained unclear.

The researchers discovered that STING acts as an ion channel, allowing protons to leak out of a cellular organelle called the Golgi body. This makes STING the first human immune sensor capable of translating danger signals into ion flow. The team connected previous findings that STING or proton flux could activate autophagy and inflammasome formation, leading them to hypothesize that STING initiates or mediates proton flux to trigger these downstream processes.

The study’s findings have significant implications for the development of drugs that can modulate STING activity. STING is a crucial factor in triggering immune responses in infection, autoimmunity, and cancer. Drugs that activate STING have been tested in clinical trials as potential cancer immunotherapy treatments. Understanding STING’s ion channel activity opens up new possibilities for designing therapeutics to regulate STING and its associated pathways.

The researchers used a molecule called C53, which blocks the putative pore of the STING protein, to inhibit proton leakage and prevent autophagy and inflammasome formation while still activating interferon production. This selective control could be valuable in treating inflammatory diseases where STING is overactivated.

Further studies will explore the relative importance of the three pathways activated by STING and investigate whether STING influences other cellular activities controlled by ion channels. The research was funded by the U.S. National Institutes of Health, the Howard Hughes Medical Institute, and other organizations.

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