Key result
STING interacts with G3BP1 and UBAP2L to promote stress granule pre-condensation, driving ALS-associated TDP-43 pathology.
Why the study?
How ER-localized stress granule assembly is organized and regulated remains unclear, and whether the innate immune adaptor STING is linked to stress granule regulation has not been established.
STING acts as an ER-resident scaffold protein that promotes stress granule pre-condensation and maturation, contributing to cell survival under stress and potentially exacerbating ALS-associated TDP-43 pathology.
Answers are grounded in this paper and cite their sources.
STING inhibition may warrant exploration in ALS; extends its functions beyond innate immunity to ER stress granule regulation in models.
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.
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Eom et al. (2026) studied Amyotrophic lateral sclerosis (ALS) and cellular stress. STING knockout or mutation vs. Wild-type (WT) control was evaluated on Stress granule formation and maturation. STING acts as an endoplasmic reticulum-resident scaffold protein that interacts with G3BP1 and UBAP2L to promote stress granule pre-condensation, contributing to ALS-associated TDP-43 pathology.
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