Targeted stress granule regulation by engineering a non-catalytic O-GlcNAc transferase.

ABSTRACT: Stress granules (SGs) are disease-relevant dynamic ribonucleoprotein condensates formed by liquid-liquid phase separation (LLPS) of proteins and mRNAs. Understanding their regulators and developing interventions are critical for therapeutic development. O-GlcNAc transferase (OGT) has been implicated in SG regulation, but functions beyond O-GlcNAcylation remain unclear. Here we uncover that, upon induced proximity, OGT suppresses LLPS of the SG marker G3BP1 and thereby SG assembly, independent of its catalytic activity. We repurpose OGT into an SG modulator by fusing its N-catalytic and intervening domains (NI) to induced-proximity modules. This inhibitory effect arises from targeted protein immobilization that rigidifies G3BP1 under prolonged stress. This tool recognizes G3BP1's domain org

SUBMITTER: Wang N 

PROVIDER: S-EPMC12779947 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature