Despite its painful sounding name, the stimulator of interferon genes protein, known as STING, is something you want to have around. When active, STING helps ramp up production of inflammatory proteins called interferons and cytokines, jump starting a part of the immune system.
STING was originally identified for its role in antiviral immunity but multiple companies want to find ways to activate STING to sic immune cells on tumors. At the University of Texas Southwestern Medical Center, researchers have used structural biology to reveal more about how STING turns on and how the protein activates a cellular tidyup (Nature 2019, DOI: 10.1038/s41586-019-1000-2, 10.1038/s41586-019-1006-9, and s41586-019-0998-5). The images of these membrane-bound proteins provide scientists with new information to guide the development of molecules to target STING.
Zhijian Chen and coworkers used cryo-electron microscopy, or cryo-EM, to get their structural snapshots of STING. They observed how human and chicken STING proteins arrange themselves in cell membranes when inactive and how the chicken STING changes when activated. The team imaged the chicken STING protein bound to a protein called TBK1, which active STING binds to as part of the process of ramping up the immune system. The scientists also explored how a separate pathway without TBK1 can start the cell’s internal clean up operation, called autophagy.
In another study, the team investigated how STING changes shape when it is activated by a cyclic dinucleotide known as cGAMP. STING is a dimer of two protein subunits. When inactive, the parts of the subunits that sit outside of the membrane wrap around each other. When cGAMP binds, the two subunits straighten up so that the each takes hold of one side of the dinucleotide. This change makes the dimer more compact, allowing the dimers to stack up, side by side in the membrane.
That side-by-side structure is the same as one reported in a recent preprint from Lingyin Li’s group at Stanford University that proposes mechanisms for STING activation, inhibition, and hyperactivation (BioRxiv 2019 DOI: 10.1101/552166). Working on human STING, Li’s team also showed that another STING activator, c-di-GMP, has a different effect on the protein’s conformation and partially blocks cGAMP’s ability to turn on STING.
Li says she thinks the two groups’ work complement each other. They are, she adds, “big news for STING drug discovery because we now know how cGAMP activates STING and not all STING agonists are created equal.” Li adds that the data from Chen’s team provides structural explanations for some previous biochemical data on STING.
Andrea Ablasser of the Global Health Institute at the Swiss Federal Institute of Technology, Lausanne (EPFL) points out that there are still many unanswered questions about STING, including how the cell regulates both the protein’s movements and the autophagy pathway that Chen’s team identified. However, she adds, the high resolution cryo-EM data provided by Chen’s team will be useful for drug-discovery programs.
CORRECTION: This story was updated on Mar. 8, 2019, to correct the spelling of Lingyin Li's name.