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
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.
J Exp Med. 2017 Apr 3;214(4):1093-1109. doi: 10.1084/jem.20161105. Epub 2017 Mar 9.
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.
信号转导与转录激活因子3（STAT3）是肠道炎症和肿瘤发生的关键介质。然而，调节STAT3磷酸化和激活的分子机制尚未完全清楚。在此，我们证明在苏氨酸717（T717）上对STAT3进行O-连接的β-N-乙酰葡糖胺（O-GlcNAc）修饰会负向调节其磷酸化，并影响巨噬细胞中靶基因的表达。我们进一步发现，泛素连接酶家族E3泛素连接酶cullin 3（CUL3）下调O-GlcNAc转移酶（OGT）的表达并抑制STAT3的O-GlcNAc化。CUL3对OGT表达的抑制作用依赖于核因子E2相关因子2（Nrf2），Nrf2与OGT启动子区域结合并增加基因转录。在髓系细胞中敲除CUL3会导致结肠巨噬细胞中STAT3磷酸化缺陷，同时伴有结肠炎症加剧和炎症驱动的肿瘤发生。因此，本研究确定了一种新的STAT3翻译后修饰形式，可调节其磷酸化，并提示免疫代谢在结肠炎症和肿瘤发生中的重要性。
