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

Xinghui Li, Zhibin Zhang, Lupeng Li, Wei Gong, Audrey J Lazenby, Benjamin J Swanson, Laura E. Herring, John M. Asara, Jeffrey D. Singer, Haitao Wen

Research output: Contribution to journalArticle

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Abstract

Signal transducer and activator of transcription 3 (STAT3) is a key mediator of intestinal inflammation and tumorigenesis. However, the molecular mechanism that modulates STAT3 phosphorylation and activation is not fully understood. Here, we demonstrate that modification of STAT3 with O-linked β-N-acetylglucosamine (O-GlcNAc) on threonine 717 (T717) negatively regulates its phosphorylation and targets gene expression in macrophages. We further found that cullin 3 (CUL3), a cullin family E3 ubiquitin ligase, down-regulates the expression of the O-GlcNAc transferase (OGT) and inhibits STAT3 OGlcNAcylation. The inhibitory effect of CUL3 on OGT expression is dependent on nuclear factor E2-related factor-2 (Nrf2), which binds to the Ogt promoter region and increases gene transcription. Myeloid deletion of Cul3 led to defective STAT3 phosphorylation in colon macrophages, which was accompanied by exacerbated colonic inflammation and inflammation-driven tumorigenesis. Thus, this study identifies a new form of posttranslational modification of STAT3, modulating its phosphorylation, and suggests the importance of immunometabolism on colonic inflammation and tumorigenesis.

Original languageEnglish (US)
Pages (from-to)1093-1109
Number of pages17
JournalJournal of Experimental Medicine
Volume214
Issue number4
DOIs
StatePublished - Apr 1 2017

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Cullin Proteins
STAT3 Transcription Factor
Phosphorylation
Inflammation
Carcinogenesis
Macrophages
NF-E2-Related Factor 2
Inflammation Mediators
Ubiquitin-Protein Ligases
Acetylglucosamine
Threonine
Post Translational Protein Processing
Genetic Promoter Regions
O-GlcNAc transferase
Colon
Down-Regulation
Gene Expression
Genes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Myeloid-derived cullin 3 promotes STAT3 phosphorylation by inhibiting OGT expression and protects against intestinal inflammation. / Li, Xinghui; Zhang, Zhibin; Li, Lupeng; Gong, Wei; Lazenby, Audrey J; Swanson, Benjamin J; Herring, Laura E.; Asara, John M.; Singer, Jeffrey D.; Wen, Haitao.

In: Journal of Experimental Medicine, Vol. 214, No. 4, 01.04.2017, p. 1093-1109.

Research output: Contribution to journalArticle

Li, Xinghui ; Zhang, Zhibin ; Li, Lupeng ; Gong, Wei ; Lazenby, Audrey J ; Swanson, Benjamin J ; Herring, Laura E. ; Asara, John M. ; Singer, Jeffrey D. ; Wen, Haitao. / Myeloid-derived cullin 3 promotes STAT3 phosphorylation by inhibiting OGT expression and protects against intestinal inflammation. In: Journal of Experimental Medicine. 2017 ; Vol. 214, No. 4. pp. 1093-1109.
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