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

Jiazhen Zhang, Thomas Macartney, Mark Peggie, Philip Cohen (Lead / Corresponding author)

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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 TAK1 by interacting with its TAB2 and TAB3 subunits. Here, we report that IL-1β can also activate the TAB1-TAK1 heterodimer present in TAB2/TAB3 double knock-out (DKO) IL-1 receptor-expressing cells. The IL-1β-dependent activation of the TAB1- TAK1 heterodimer in TAB2/3 DKO cells required the expression and E3 ligase activity of TRAF6 and was reduced by the siRNA knock-down of Ubc13, an E2 conjugating enzyme that directs the formation of K63-Ub chains. IL-1β signaling was restored to TAB1/2/3 triple KO cells by the re-expression of either TAB1 or TAB2, but not by a ubiquitin-binding-defective mutant of TAB2. We conclude that IL-1β 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-1β-stimulated, TAK1-dependent activation of p38α MAP kinase and the canonical IKK complex, as well as the NF-κBdependent transcription of immediate early genes was similar in TAB2/3 DKO and TAB2/3-expressing cells. However, in contrast to TAB2/3-expressing cells, IL-1β signaling was transient in TAB2/3 DKO cells and the activation of JNK1, JNK2 and p38γ 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 p38γ MAP kinases. These observations and the transient activation of the TAB1-TAK1 heterodimer may explain why IL-1β-dependent IL-8 mRNA formation was abolished in TAB2/3 DKO cells.
Original languageEnglish
Pages (from-to)2235-2248
Number of pages16
JournalBiochemical Journal
Volume474
Issue number13
Early online date15 May 2017
DOIs
Publication statusPublished - 26 Jul 2017

Keywords

  • TAK1
  • TRAF6
  • TAB1
  • TAB2
  • Interleukin-1
  • ubiquitin

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  • Student Theses

    An investigation of the activation of protein kinase complexes in the MyD88 signalling network

    Author: Zhang, J., 2017

    Supervisor: Cohen, P. (Supervisor)

    Student thesis: Doctoral ThesisDoctor of Philosophy

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    • MRC PPU - Research Professor & Personal Chair in Enzymology

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