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EMBO J. 2012 Mar 21;31(6):1394-404. doi: 10.1038/emboj.2012.8. Epub 2012 Feb 3.

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

Author information

1
Division of Cell Signalling and Immunology, College of Life Sciences, University of Dundee, Dundee, UK.

Abstract

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.

PMID:
22307082
PMCID:
PMC3321193
DOI:
10.1038/emboj.2012.8
[Indexed for MEDLINE]
Free PMC Article

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