"The Downregulation of STING Signaling"
The innate immune STING pathway is essential for antiviral and anticancer immunity, but its aberrant activation underpins a broad spectrum of autoimmune conditions and ageing-related neuroinflammation. STING inhibitors are therefore highly sought therapeutics, but their development has met with limited success because we do not fully understand the mechanisms that regulate STING and the most efficacious mechanism to target. We use biochemistry, cell and chemical biology to elucidate how STING is activated and negatively regulated. We discovered that cGAMP, the second messenger that activates STING, can be lysosomally sequestered to restrict access to STING. On STING itself, cysteine post-translational modifications restrain signaling in the basal state, and upon activation communicate allosterically to aid a signaling-competent assembly of STING oligomers, making the disruption of STING oligomerization the most viable target mechanism for inhibitors. We further disclose an on-target cyclic peptide that inhibits STING oligomerization, using crystallography to reveal its binding site, a previously undescribed pocket on the STING surface. Together, we reveal that the negative regulation of STING occurs endogenously in a broader scale than previous expected, opening new avenues and targets for the development of inhibitors.