O-GlcNAcylation of TAB1 modulates TAK1-mediated cytokine release.

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 transforming growth factor-β, tumour necrosis factor (TNF), interleukin-1 (IL-1) and wnt family ligands. TAK1 is found in complex with binding partners TAB1-3, phosphorylation and ubiquitination of which has ...
been found to regulate TAK1 activity. In this study, we show that TAB1 is modified with N-acetylglucosamine (O-GlcNAc) on a single site, Ser395. With the help of a novel O-GlcNAc site-specific antibody, we demonstrate that O-GlcNAcylation of TAB1 is induced by IL-1 and osmotic stress, known inducers of the TAK1 signalling cascade. By reintroducing wild-type or an O-GlcNAc-deficient mutant TAB1 (S395A) into Tab1(-/-) mouse embryonic fibroblasts, we determined that O-GlcNAcylation of TAB1 is required for full TAK1 activation upon stimulation with IL-1/osmotic stress, for downstream activation of nuclear factor κB and finally production of IL-6 and TNFα. This is one of the first examples of a single O-GlcNAc site on a signalling protein modulating a key innate immunity signalling pathway.
Mesh Terms:
Acylation, Adaptor Proteins, Signal Transducing, Animals, Cells, Cultured, Fibroblasts, HEK293 Cells, Humans, Interleukin-1, Interleukin-6, MAP Kinase Kinase Kinases, Mice, NF-kappa B, Osmotic Pressure, Phosphorylation, Phosphotransferases (Alcohol Group Acceptor), Protein Transport, Protein-Serine-Threonine Kinases, Signal Transduction, Tumor Necrosis Factor-alpha
EMBO J.
Date: Mar. 21, 2012
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