Article type:
Research
Estimated read time:
3 mins min read
Published:
26/09/2025
This study provides key evidence for how the protein Stimulator of Interferon Genes (STING) is activated in cells by infection and by genetic variants and how excessive activation could be prevented
Date of publication:
17/2/26
Author:
Roger Brooks
Category:
STING biology
Plain Language
This study explains how a key immune system protein called STING (Stimulator of Interferon Genes) is switched on and off. STING normally helps the body fight infections, but if it is stuck in the “on” position it can cause serious inflammation and rare childhood diseases including STING-associated vasculopathy with onset in infancy (SAVI). The researchers showed that STING becomes active by forming chains of the STING molecule (polymers) inside cells. Some genetic changes cause STING to form these chains all the time, which explains why affected children develop severe inflammation. The study also shows that certain molecules can partly block STING activity, suggesting future treatments may be possible.
Why it Matters
This work provides a molecular explanation for how STING is tightly regulated under normal conditions and why specific mutations cause uncontrolled interferon production in autoinflammatory disease. By identifying polymer formation through C148-dependent disulfide bonding as essential steps in signalling, the study clarifies how innate immune responses achieve a high activation threshold while avoiding inappropriate responses to self-DNA. It also links structural abnormalities directly to human pathology such as SAVI.
Hope for the Future
The discovery that alternative STING conformations can partially inhibit signalling suggests a new therapeutic strategy: designing molecules that prevent or destabilise pathogenic STING polymers without completely blocking antiviral immunity. Such targeted inhibitors could potentially reduce chronic inflammation in interferon-mediated diseases while preserving host defence against infections and cancer.
Read More:
Background STING is a central adaptor protein in cytosolic DNA sensing and innate immune signalling. Upon detection of double-stranded DNA by cGAS, the second messenger 2’3’-cGAMP is generated and binds STING, leading to recruitment of TBK1 and phosphorylation of IRF3, with subsequent induction of type I interferons. While STING is essential for antiviral and antitumour immunity, excessive or constitutive activation causes autoinflammatory disease, including SAVI. Prior to this work, the structural mechanism by which ligand binding activates STING and how disease-causing mutations produce hyperactivation remained poorly understood.
What the Study Found Using X-ray crystallography, Small-Angle X-ray Scattering (SAXS), biochemical assays, and cell-based experiments, the authors demonstrated that ligand binding induces closure of the STING homodimer and release of its C-terminal tail (CTT), exposing a polymerization interface. Activated STING assembles into ordered linear polymers on the endoplasmic reticulum. Polymerization is stabilized by intermolecular disulfide bonds mediated by cysteine 148 (C148).
Disease-causing SAVI mutations either disrupt sequestration of the CTT or reside within the polymer interface, resulting in constitutive polymer formation and ligand-independent signalling. The bacterial cyclic dinucleotide cyclic-di-GMP (CDG) was shown to induce an alternative active conformation of STING that signals cooperatively but can also act as a partial antagonist of cGAMP-mediated activation. These findings establish polymerization, rather than simple dimer closure, as the key structural basis of STING activation and hyperactivation.
Citation Ergun SL et al., Cell 2019 178:290-301.
Authors Ergun SL, Fernandez D, Weiss TM, Li L.
Date of publication 11/7/19