Retracted: Modification Of Tak1 By O-Linked N-Acetylglucosamine Facilitates Tak1 Activation And Promotes M1 Macrophage Polarization (Retracted Article. See Vol. 36, Pg. 267, 2017)
CELLULAR SIGNALLING(2016)
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-GIcNAcylation is an important type of post-translational modification, which subtly modulates inflammation responses. Transforming growth factor (TGF)-beta-activated kinase 1 (TAK1) is a key serine/threonine protein kinase that mediates signals transduced by pro-inflammatory cytokines such as TGF-beta, tumor necrosis factor (TNF), and interleukin-1 (IL-1). It is here reported that TGF beta-activated kinase (TAK1) is modified with N-acetylglucosamine (O-GlcNAc) on 5427. 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 S427ATAK1 mutant into macrophages, it was determined that O-GlcNAcylation of TAK1 on S427 is required for T187/5192 phosphorylation and full activation of TAK1 upon stimulation with IL-1 alpha and NaCl. Aborting O-GIcNAcylation of TAK1 on 5427 was found to inhibit the downstream JNK and nuclear factor-kappa B 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 5427 critically regulates the pro-inflammatory activation and M1 polarization of macrophages via modulation of the TAK1/JNK/NF-kappa B signaling pathway. (C) 2016 Elsevier Inc. All rights reserved.
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Key words
Macrophage, O-GlcNAcylation, Polarization, TGF beta-activated kinase 1 (TAK1)
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