Roles for TAB1 in regulating the IL-1-dependent phosphorylation of the TAB3 regulatory subunit and activity of the TAK1 complex

MRC Protein Phosphorylation Unit, University of Dundee, Dundee DD1 5EH, Scotland, UK.
Biochemical Journal (Impact Factor: 4.78). 03/2008; 409(3):711-22. DOI: 10.1042/BJ20071149
Source: PubMed

ABSTRACT The protein kinase TAK1 (transforming growth factor-beta-activated kinase 1), which has been implicated in the activation of MAPK (mitogen-activated protein kinase) cascades and the production of inflammatory mediators by LPS (lipopolysaccharide), IL-1 (interleukin 1) and TNF (tumour necrosis factor), comprises the catalytic subunit complexed to the regulatory subunits, termed TAB (TAK1-binding subunit) 1 and either TAB2 or TAB3. We have previously identified a feedback-control mechanism by which p38alpha MAPK down-regulates TAK1 and showed that p38alpha MAPK phosphorylates TAB1 at Ser(423) and Thr(431). In the present study, we identified two IL-1-stimulated phosphorylation sites on TAB2 (Ser(372) and Ser(524)) and three on TAB3 (Ser(60), Thr(404) and Ser(506)) in human IL-1R cells [HEK-293 (human embryonic kidney) cells that stably express the IL-1 receptor] and MEFs (mouse embryonic fibroblasts). Ser(372) and Ser(524) of TAB2 are not phosphorylated by pathways dependent on p38alpha/beta MAPKs, ERK1/2 (extracellular-signal-regulated kinase 1/2) and JNK1/2 (c-Jun N-terminal kinase 1/2). In contrast, Ser(60) and Thr(404) of TAB3 appear to be phosphorylated directly by p38alpha MAPK, whereas Ser(506) is phosphorylated by MAPKAP-K2/MAPKAP-K3 (MAPK-activated protein kinase 2 and 3), which are protein kinases activated by p38alpha MAPK. Studies using TAB1(-/-) MEFs indicate important roles for TAB1 in recruiting p38alpha MAPK to the TAK1 complex for the phosphorylation of TAB3 at Ser(60) and Thr(404) and in inhibiting the dephosphorylation of TAB3 at Ser(506). TAB1 is also required to induce TAK1 catalytic activity, since neither IL-1 nor TNFalpha was able to stimulate detectable TAK1 activity in TAB1(-/-) MEFs. Surprisingly, the IL-1 and TNFalpha-stimulated activation of MAPK cascades and IkappaB (inhibitor of nuclear factor kappaB) kinases were similar in TAB1(-/-), MEKK3(-/-) [MAPK/ERK (extracellular-signal-regulated kinase) kinase kinase 3] and wild-type MEFs, suggesting that another MAP3K (MAPK kinase kinase) may mediate the IL-1/TNFalpha-induced activation of these signalling pathways in TAB1(-/-) and MEKK3(-/-) MEFs.

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    • "The engagement of TLR ectodomains by cognate ligands causes the recruitment of TIR-domain-containing adaptor molecule MyD88 to the cytoplasmic TIR domains of TLRs expect TLR3, leading to successive activation of IL-1 receptor-associated kinase 4 (IRAK4), IRAK1, and tumor necrosis factor receptor-associated factor 6 (TRAF6) Akira et al., 2001; Blasius and Beutler, 2010; Besse et al., 2007. The activated IRAK1/TRAF6 complex disassociates from the receptor complex and interacts with another complex consisting of transforming growth factor (TGF)-b activated kinase 1 (TAK1) and TAK1-binding protein (TAB)1, TAB2 and TAB3 (Besse et al., 2007; Mendoza et al., 2008). Pellino, a highly conserved E3 class ubiquitin ligase in both vertebrates and invertebrates, is an upstream mediator in the TLR pathway (Moynagh, 2009; Schauvliege et al., 2006, 2007). "
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    • "Studies with Tab1-deficient mouse embryonic fibroblasts (Tab1 À/À MEFs) suggest that TAB1 plays several roles in the regulation of the TAK1 complex, namely to recruit p38a MAPK to the TAK1 complex for the phosphorylation of TAB3, to suppress the dephosphorylation of TAB3, and to induce TAK1 catalytic activity (Mendoza et al, 2008). TAB1 is a crucial mediator in TAK1 signalling as Tab1 À/À MEFs do not activate TAK1 in response to IL-1 and TNFa (Mendoza et al, 2008). MEKK3 is maintained in an inactive state by interaction with TAK1 in unstimulated cells, preventing basal NFkB signalling. "
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    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.
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