title: Modification of TAK1 by O-linked N-acetylglucosamine facilitates TAK1 activation and promotes M1 macrophage polarization.
abstract: Macrophages play many different roles in tissue inflammation and immunity, and the plasticity of macrophage polarization is closely associated with acute inflammatory responses. O-GlcNAcylation is an important type of post-translational modification, which subtly modulates inflammation responses. Transforming growth factor (TGF)-β-activated kinase 1 (TAK1) is a key serine/threonine protein kinase that mediates signals transduced by pro-inflammatory cytokines such as TGF-β, tumor necrosis factor (TNF), and interleukin-1 (IL-1). It is here reported that TGFβ-activated kinase (TAK1) is modified with N-acetylglucosamine (O-GlcNAc) on S427. Both IL-1 and osmotic stress, which are known as the TAK1-signaling inducers, significantly trigger the O-GlcNAcylation of TAK1 in macrophages. By overexpressing wild-type (WT) or S427A TAK1 mutant into macrophages, it was determined that O-GlcNAcylation of TAK1 on S427 is required for T187/S192 phosphorylation and full activation of TAK1 upon stimulation with IL-1α and NaCl. Aborting O-GlcNAcylation of TAK1 on S427 was found to inhibit the downstream JNK and nuclear factor-κB activation and reduce the final amount of cytokines produced in activated macrophages to a great extent. Results also showed that overexpression of the O-GlcNAcylation-deficient mutant of TAK1 promotes LPS-mediated apoptosis in macrophages. Importantly, TAK1 O-GlcNAcylation was found to promote M1 macrophage polarization in activated macrophages. Taken together, these data demonstrate that O-GlcNAcylation of TAK1 on S427 critically regulates the pro-inflammatory activation and M1 polarization of macrophages via modulation of the TAK1/JNK/NF-κB signaling pathway.
authors.affiliation: Department of Pathogen Biology, Medical College, Nantong University, Nantong 226001, Jiangsu Province, China; Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong 226001, Jiangsu Province, China.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Immunology, Medical College, Nantong University, Nantong 226001, Jiangsu Province, China; Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong 226001, Jiangsu Province, China.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Immunology, Medical College, Nantong University, Nantong 226001, Jiangsu Province, China; Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong 226001, Jiangsu Province, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Tao
authors.affiliation: Department of Pathogen Biology, Medical College, Nantong University, Nantong 226001, Jiangsu Province, China; Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong 226001, Jiangsu Province, China.
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Pathogen Biology, Medical College, Nantong University, Nantong 226001, Jiangsu Province, China; Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong 226001, Jiangsu Province, China.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Immunology, Medical College, Nantong University, Nantong 226001, Jiangsu Province, China.
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Ji
authors.affiliation: Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong 226001, Jiangsu Province, China.
authors.forename: Lijian
authors.initials: L
authors.lastname: Han
authors.affiliation: Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong 226001, Jiangsu Province, China.
authors.forename: Huiyuan
authors.initials: H
authors.lastname: Qiu
authors.affiliation: Department of Immunology, Medical College, Nantong University, Nantong 226001, Jiangsu Province, China.
authors.forename: Guizhou
authors.initials: G
authors.lastname: Zhu
authors.affiliation: Department of Immunology, Medical College, Nantong University, Nantong 226001, Jiangsu Province, China.
authors.forename: Yifen
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong 226001, Jiangsu Province, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong 226001, Jiangsu Province, China; Coinnovation Center of Neuroregeneration, Nantong University, Nantong 226001, Jiangsu Province, China. Electronic address: shag@ntu.edu.cn.
authors.forename: Aiguo
authors.initials: A
authors.lastname: Shen
keywords: Macrophage; O-GlcNAcylation; Polarization; TGFβ-activated kinase 1 (TAK1)