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Adv."],"published-print":{"date-parts":[[2026,5,29]]},"abstract":"<jats:p>Innate immune and stress responses must be tightly regulated to prevent aberrant activation in the absence of pathogens. The RNA helicase DHX36 has been implicated in viral RNA sensing, but its role in immune regulation is not fully understood. Here, we show that DHX36 functions as a rheostat that restrains immune activation under homeostatic conditions while modulating antiviral signaling. Exposure to double-stranded RNA reduces DHX36 activity, enabling immune activation. In contrast, cells lacking DHX36 adopt a constitutively activated immune state characterized by accumulation of RNA G-quadruplex structures, protein kinase R (PKR)\u2013dependent stress granule formation, and elevated interferon-stimulated gene expression. These cells also display enhanced responsiveness to the viral RNA sensor retinoic acid\u2013inducible gene I (RIG-I) and more effectively suppress replication of a yellow fever virus replicon. 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