STING is the scaffold protein for stress granule pre-condensation at the ER.

Stress granules (SGs) are dynamic, membraneless ribonucleoprotein condensates that assemble in response to cellular stress and coordinate diverse cellular stress responses and diseases. Although SG have been reported to associate with the endoplasmic reticulum (ER), how ER-localized stress granule assembly is organized and regulated remains unclear. STING (stimulator of interferon genes) is a central innate immune adaptor that has recently been implicated in diverse non-canonical cellular functions, yet its potential link to SG regulation has not been established. Independent of its canonical functions in innate immune signaling, we identified a novel role of STING as a regulator of SG formation. We found that prior to stress stimulation, STING interacts with key SG core components G3BP1 and UBAP2L via its C-terminal domain (CTD) at the ER, forming a pre-condensation complex that facilitates SG maturation in response to stress. Loss of STING reduces SG formation and increases stress-induced cell death, whereas ER-anchored STING CTD is sufficient to reverse them. Mechanistically, STING enhances basal interactions between G3BP1 and UBAP2L, lowering the threshold for SG maturation upon stress. In addition, STING promotes the pathologic effects of TDP-43 mutations associated with amyotrophic lateral sclerosis. Our findings implicate STING as an ER-resident regulator of SG dynamics that contributes to neurodegenerative pathology, highlighting it as a potential therapeutic target in diseases associated with aberrant SG assembly.