title: Myeloid-derived cullin 3 promotes STAT3 phosphorylation by inhibiting OGT expression and protects against intestinal inflammation.
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 withO-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 theO-GlcNAc transferase (OGT) and inhibits STAT3O-GlcNAcylation. The inhibitory effect of CUL3 on OGT expression is dependent on nuclear factor E2-related factor-2 (Nrf2), which binds to theOgtpromoter region and increases gene transcription. Myeloid deletion ofCul3led 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.
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198.|Holland Regenerative Medicine Program, University of Nebraska Medical Center, Omaha, NE 68198.
authors.forename: Xinghui
authors.initials: X
authors.lastname: Li
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115.
authors.forename: Zhibin
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198.|Holland Regenerative Medicine Program, University of Nebraska Medical Center, Omaha, NE 68198.
authors.forename: Lupeng
authors.identifier: 0000-0003-3455-8179
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198.|Holland Regenerative Medicine Program, University of Nebraska Medical Center, Omaha, NE 68198.|Department of Hepatobiliary Surgery and Liver Transplantation, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Gong
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198.
authors.forename: Audrey J
authors.initials: AJ
authors.lastname: Lazenby
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Swanson
authors.affiliation: Proteomics Core Facility, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
authors.forename: Laura E
authors.identifier: 0000-0003-4496-7312
authors.initials: LE
authors.lastname: Herring
authors.affiliation: Division of Signal Transduction, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, MA 02115.
authors.forename: John M
authors.initials: JM
authors.lastname: Asara
authors.affiliation: Department of Biology, Portland State University, Portland, OR 97201.
authors.forename: Jeffrey D
authors.identifier: 0000-0002-0654-3036
authors.initials: JD
authors.lastname: Singer
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198 haitao.wen@unmc.edu.|Holland Regenerative Medicine Program, University of Nebraska Medical Center, Omaha, NE 68198.
authors.forename: Haitao
authors.identifier: 0000-0002-6363-2748
authors.initials: H
authors.lastname: Wen
mesh_terms: D000818:Animals; D044842:Cullin Proteins / Q000502:physiology*; D004751:Enteritis / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D017351:N-Acetylglucosaminyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D050796:STAT3 Transcription Factor / Q000378:metabolism*
chemical_list: C503646:Cul3 protein, mouse; D044842:Cullin Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase