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Interleukin-1 and TRAF6-dependent activation of TAK1 in the absence of TAB2 and TAB3.

ABSTRACT: Interleukin-1 (IL-1) signaling induces the formation of Lys63-linked ubiquitin (K63-Ub) chains, which are thought to activate the 'master' protein kinase TGF?-activated kinase 1 (TAK1) by interacting with its TAK1-binding 2 (TAB2) and TAB3 subunits. Here, we report that IL-1? can also activate the TAB1-TAK1 heterodimer present in TAB2/TAB3 double knockout (DKO) IL-1 receptor-expressing cells. The IL-1?-dependent activation of the TAB1-TAK1 heterodimer in TAB2/3 DKO cells is required for the expression and E3 ligase activity of tumor necrosis factor receptor-associated factor 6 (TRAF6) and is reduced by the small interfering RNA (siRNA) knockdown of ubiquitin conjugating 13 (Ubc13), an E2-conjugating enzyme that directs the formation of K63-Ub chains. IL-1? signaling was restored to TAB1/2/3 triple KO cells by the re-expression of either TAB1 or TAB2, but not by an ubiquitin binding-defective mutant of TAB2. We conclude that IL-1? can induce the activation of TAK1 in two ways, only one of which requires the binding of K63-Ub chains to TAB2/3. The early IL-1?-stimulated, TAK1-dependent activation of p38? mitogen-activated protein (MAP) kinase and the canonical I?B kinase (IKK) complex, as well as the NF-?B-dependent transcription of immediate early genes, was similar in TAB2/3 DKO cells and TAB2/3-expressing cells. However, in contrast with TAB2/3-expressing cells, IL-1? signaling was transient in TAB2/3 DKO cells, and the activation of c-Jun N-terminal kinase 1 (JNK1), JNK2 and p38? was greatly reduced at all times. These observations indicate a role for TAB2/3 in directing the TAK1-dependent activation of MAP kinase kinases that switch on JNK1/2 and p38? MAP kinases. These observations and the transient activation of the TAB1-TAK1 heterodimer may explain why IL-1?-dependent IL-8 mRNA formation was abolished in TAB2/3 DKO cells.

SUBMITTER: Zhang J

PROVIDER: S-EPMC5632801 | biostudies-other | 2017 Jun

REPOSITORIES: biostudies-other

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Interleukin-1 and TRAF6-dependent activation of TAK1 in the absence of TAB2 and TAB3.

Zhang Jiazhen J Macartney Thomas T Peggie Mark M Cohen Philip P

The Biochemical journal 20170626 13

Interleukin-1 (IL-1) signaling induces the formation of Lys63-linked ubiquitin (K63-Ub) chains, which are thought to activate the 'master' protein kinase TGFβ-activated kinase 1 (TAK1) by interacting with its TAK1-binding 2 (TAB2) and TAB3 subunits. Here, we report that IL-1β can also activate the TAB1-TAK1 heterodimer present in TAB2/TAB3 double knockout (DKO) IL-1 receptor-expressing cells. The IL-1β-dependent activation of the TAB1-TAK1 heterodimer in TAB2/3 DKO cells is required for the expr ...[more]

PMID: 28507161

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Project description:We recently reported that oral administration of a (+)-vitisin A-enriched product prepared from Vitis thunbergii obviously ameliorated bone loss in ovariectomized mice and (+)-vitisin A was able to inhibit receptor activator of NF-?B ligand (RANKL)-induced osteoclast differentiation in RAW264.7 cells. Here we further clarified the mechanism(s) by which (+)-vitisin A targets osteoclastic differentiation and activity. Osteoclast-characteristic enzyme activity was determined using gel zymography or spectroflurometric-based assay. Expression of signal molecules was analyzed via Western blot or immunoprecipitation. Results showed that (+)-vitisin A suppressed RANKL-induced multinuclear cells (MNCs) formation and bone resorption which was accompanied with reduction in ?3 integrin, osteoclast stimulatory transmembrane protein (OC-STAMP), matrix metalloproteinase-9 (MMP-9) and cathepsin K proteins expression. (+)-Vitisin A also down-regulated the proteolytic activities of MMP-9 and cathepsin K via targeting at the late stage function. (+)-Vitisin A prominently abrogated RANKL-triggered nuclear translocations of NF-?B, AP-1 (c-Fos/c-Jun dimer) and associated induction and nuclear accumulation of nuclear factor of activated T cells c1 (NFATc1). The upstream I?B degradation as well as ERK and JNK phosphorylation were also substantially repressed. Transfection with siRNA targeting tumor necrosis factor receptor associated factor 6 (TRAF6) clearly restrained RANKL-induced MNCs formation and NFATc1 induction. Interesting, RANKL triggered poly-ubiquitination of TRAF6 and associated TRAF6-TAK1 (transforming growth factor ?-activated kinase 1) complex formation was prominently attenuated by (+)-vitisin A. Furthermore, the interaction between c-src tyrosine kinase (c-Src) and ?3 was markedly induced by RANKL stimulation. (+)-Vitisin A significantly attenuated this interaction when concomitant treated with RANKL in RAW264.7 cells, but failed to affect c-Src/?3 complex formation when post-cultured with MNCs. Taken together, (+)-vitisin A suppressed bone resorption possibly via interruption of RANKL-induced TRAF6 ubiquitination and associated downstream signaling pathways. Furthermore, action through negative regulation of the proteolytic activity of MMP-9 and cathepsin K might also contribute to the anti-resorption effect of (+)-vitisin A.

Dataset Information

Interleukin-1 and TRAF6-dependent activation of TAK1 in the absence of TAB2 and TAB3.

Publications

Interleukin-1 and TRAF6-dependent activation of TAK1 in the absence of TAB2 and TAB3.

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