Myeloid-derived cullin 3 promotes STAT3 phosphorylation by inhibiting OGT expression and protects against intestinal...

Area of Science:

• Immunology
• Molecular Biology
• Metabolism

Background:

• Signal transducer and activator of transcription 3 (STAT3) is crucial in intestinal inflammation and tumorigenesis.
• The precise molecular mechanisms controlling STAT3 phosphorylation and activation remain incompletely understood.

Purpose of the Study:

• To investigate the role of O-linked β-N-acetylglucosamine (O-GlcNAc) modification in regulating STAT3 activity.
• To elucidate the molecular pathway involving Cullin 3 (CUL3) and its impact on STAT3 O-GlcNAcylation and intestinal inflammation.

Main Methods:

• Investigated STAT3 O-GlcNAcylation at threonine 717 (T717).
• Assessed the effect of Cullin 3 (CUL3) on O-GlcNAc transferase (OGT) expression and STAT3 O-GlcNAcylation.
• Utilized myeloid-specific Cul3 deletion mouse models to study colonic inflammation and tumorigenesis.
• Examined the role of nuclear factor E2-related factor-2 (Nrf2) in CUL3-mediated OGT regulation.

Main Results:

• O-GlcNAcylation of STAT3 at T717 negatively regulates its phosphorylation and target gene expression in macrophages.
• CUL3 down-regulates OGT expression, thereby inhibiting STAT3 O-GlcNAcylation.
• CUL3's inhibition of OGT expression is dependent on Nrf2, which enhances Ogt gene transcription.
• Myeloid deletion of Cul3 resulted in impaired STAT3 phosphorylation in colon macrophages, leading to exacerbated colonic inflammation and inflammation-driven tumorigenesis.

Conclusions:

• Identified a novel posttranslational modification of STAT3 (O-GlcNAcylation) that modulates its phosphorylation.
• Demonstrated a regulatory pathway where CUL3, Nrf2, and OGT influence STAT3 activity in macrophages.
• Highlighted the significance of immunometabolism in the context of colonic inflammation and tumorigenesis, suggesting therapeutic potential.