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 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 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-1β 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-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 mitogen-activated protein (MAP) kinase and the canonical IκB kinase (IKK) complex, as well as the NF-κB-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-1β signaling was transient in TAB2/3 DKO cells, and the activation of c-Jun N-terminal kinase 1 (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.
Highlights
Interleukin-1 (IL-1) has a central role in regulating immune and inflammatory responses to infection and tissue damage [1]
The expression of tumor necrosis factor receptorassociated factor 6 (TRAF6) is required for IL-1 signaling and, until recently, it was thought that the essential role of TRAF6 in this pathway was to generate the Lys63-linked ubiquitin (K63-Ub) chains that interact with TAK1-binding 2 (TAB2)/3 and induce the activation of the TAK1-binding protein 1 (TAB1)–TGFβ-activated kinase 1 (TAK1)–TAB2 and TAB1–TAK1–TAB3 heterotrimers
We recently found that the E3 ligase activity of TRAF6 contributes to, but is not essential for IL-1 and Toll-like receptor (TLR) signaling, and that the essential roles of TRAF6 are independent of its E3 ligase activity
Summary
Interleukin-1 (IL-1) has a central role in regulating immune and inflammatory responses to infection and tissue damage [1]. IL-1 signaling is initiated by the recruitment of MyD88 (Myeloid Differentiation primary response gene 88) to the IL-1 receptor (IL-1R) complex, which is followed by the interaction of IL-1R-associated kinase 4 (IRAK4) with MyD88 and IRAK1 and/or IRAK2 with IRAK4, to form an oligomeric complex termed the Myddosome [2,3]. It interacts with tumor necrosis factor receptorassociated factor 6 (TRAF6) [4] and induces its dimerization and activation [5]. It phosphorylates Pellino and Pellino, converting them from inactive into active E3 ligases [6,7,8]. The pseudokinase IRAK2, which lacks kinase catalytic activity, can activate TRAF6 [10], but would not be expected to be capable of activating Pellino and Pellino2 [9]
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