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

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 -linked β- -ac...

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Bibliographic Details
Published in:The Journal of experimental medicine 2017-04, Vol.214 (4), p.1093-1109
Main Authors: 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
Format: Article
Language:English
Subjects:
Animals
Auditory defects
Cancer
Colitis
Colon
Cullin
Cullin Proteins - physiology
Enteritis - prevention & control
Gene deletion
Gene expression
Inflammation
Inflammatory bowel disease
Interleukin 10
Intestine
Macrophages
Mice
Mice, Inbred C57BL
N-Acetylglucosamine
N-Acetylglucosaminyltransferases - antagonists & inhibitors
N-Acetylglucosaminyltransferases - metabolism
O-GlcNAcylation
Phosphorylation
Protein Processing, Post-Translational
Signaling
Stat3 protein
STAT3 Transcription Factor - metabolism
Threonine
Transcription
Tumorigenesis
Ubiquitin
Ubiquitin-protein ligase
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Summary: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 -linked β- -acetylglucosamine ( -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 -GlcNAc transferase (OGT) and inhibits STAT3 -GlcNAcylation. The inhibitory effect of CUL3 on OGT expression is dependent on nuclear factor E2-related factor-2 (Nrf2), which binds to the promoter region and increases gene transcription. Myeloid deletion of 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.
ISSN:0022-1007
1540-9538
DOI:10.1084/jem.20161105