Study finds a surprising new role for a major immune regulator STING

Good news! Get out the STING! 😊

"A signaling protein known as STING is a critical player in the human immune system, detecting signs of danger within cells and then activating a variety of defense mechanisms.

STING is primarily on the lookout for DNA, which can indicate either a foreign invader such as a virus or damage to the host tissue or cell. When STING detects that danger signal, it can turn on at least three different pathways — one leading to interferon production, one to non-canonical autophagy (involved in recycling cell components and clearing pathogens), and a third to formation of the inflammasome, a complex of proteins that activates inflammatory responses. The mechanism by which STING stimulates interferon production is well characterized, but it has not been understood how it activates the other two processes. ...

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. Drugs that activate STING have been developed and tested in clinical trials as cancer immunotherapy drugs that would help stimulate the immune system to destroy tumors. ..."

From the editor's summary and abstract:

"Editor’s summary

Stimulator of Interferon Genes (STING) is an innate immune sensor that activates noncanonical autophagy and the inflammasome. The exact mechanisms involved in this process are unclear, but proton leakage from organelles appears to be a common feature. Liu et al. analyzed STING’s structure, hypothesizing that its transmembrane domain forms a pore capable of proton transport. The authors used intracellular pH measurements and cell-free proteoliposome assays to show that STING can transport protons across membranes. Furthermore, this activity and STING’s proton leakage–dependent downstream functions were inhibited by a small molecule that binds at the pore. —Stella M. Hurtley

Abstract

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. 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. Compound 53 (C53), a STING agonist that binds the putative channel interface, blocked STING-induced proton flux in the Golgi and in liposomes. STING-induced LC3B lipidation and inflammasome activation were also inhibited by C53, suggesting that STING’s channel activity is critical for these two processes. Thus, STING’s interferon-induction function can be decoupled from its roles in LC3B lipidation and inflammasome activation."

Study finds a surprising new role for a major immune regulator | MIT News | Massachusetts Institute of Technology 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.

Human STING is a proton channel (no public access)

STING signalling. Can you find the STING?