2. Academic Validation
  3. Targeted stress granule regulation by engineering a non-catalytic O-GlcNAc transferase

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

  • Nat Commun. 2026 Jan 7;17(1):163. doi: 10.1038/s41467-025-66689-6.
Na Wang 1 2,  Fanjia Hou 3,  Sihui Ma 2,  Silan Liu 2 4 5,  Haimei Wei 2 4 5,  Weicheng Fang 2 4 5,  Ke Zhang 3 4,  Yun Ge 6 7 8
Affiliations

Affiliations

  • 1 State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China.
  • 2 Institute of Chemical Biology, Shenzhen Bay Laboratory, Shenzhen, China.
  • 3 Institute of Neurological and Psychiatric Disorders, Shenzhen Bay Laboratory, Shenzhen, China.
  • 4 Shenzhen Medical Academy of Research and Translation (SMART), Shenzhen, China.
  • 5 Westlake University, Hangzhou, China.
  • 6 State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China. [email protected].
  • 7 Institute of Chemical Biology, Shenzhen Bay Laboratory, Shenzhen, China. [email protected].
  • 8 Shenzhen Medical Academy of Research and Translation (SMART), Shenzhen, China. [email protected].
PMID: 41501012 DOI: 10.1038/s41467-025-66689-6
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 organization, thus generalizes to four additional proteins featuring similar architectures, suppressing condensate formation with mobility reduction. This modular, genetically encoded strategy enables SG regulation and functional dissection by interfering material properties of critical SG proteins and illuminates the cryptic non-catalytic function of OGT.

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