TAK1 is a ubiquitin-dependent kinase of MKK and IKK

Abstract

TRAF6 is a signal transducer that activates IkappaB kinase (IKK) and Jun amino-terminal kinase (JNK) in response to pro-inflammatory mediators such as interleukin-1 (IL-1) and lipopolysaccharides (LPS). IKK activation by TRAF6 requires two intermediary factors, TRAF6-regulated IKK activator 1 (TRIKA1) and TRIKA2 (ref. 5). TRIKA1 is a dimeric ubiquitin-conjugating enzyme complex composed of Ubc13 and Uev1A (or the functionally equivalent Mms2). This Ubc complex, together with TRAF6, catalyses the formation of a Lys 63 (K63)-linked polyubiquitin chain that mediates IKK activation through a unique proteasome-independent mechanism. Here we report the purification and identification of TRIKA2, which is composed of TAK1, TAB1 and TAB2, a protein kinase complex previously implicated in IKK activation through an unknown mechanism. We find that the TAK1 kinase complex phosphorylates and activates IKK in a manner that depends on TRAF6 and Ubc13-Uev1A. Moreover, the activity of TAK1 to phosphorylate MKK6, which activates the JNK-p38 kinase pathway, is directly regulated by K63-linked polyubiquitination. We also provide evidence that TRAF6 is conjugated by the K63 polyubiquitin chains. These results indicate that ubiquitination has an important regulatory role in stress response pathways, including those of IKK and JNK.

Down-Regulation of TLR9 Expression Affects the Maturation and Function of Murine Bone Marrow-Derived Dendritic Cells Induced by CpG

“…Its intracellular signaling pathway has been elucidated at the molecular level. Upon CpG binding, TLR9 associates with the adaptor molecule MyD88 to initiate CpG-dependent effects via signal transducing proteins such as members of the IL-1 receptor-associated kinase (IRAK) family, mitogen activated kinases (MAPK), or IFN regulatory factors (11)(12)(13). These events lead to the activation of nuclear factor κB (NF-κB) transcription factors, cytokine production, or expression of co-stimulatory molecules in immune cells (14).…”

RIP kinases: key decision makers in cell death and innate immunity

“…[21][22][23][24] TRAF2 25,26 and cIAPs [27][28][29][30] catalyse the polyubiquitination of RIP1. The ubiquitin-decorated RIP1 is recognized by ubiquitin-binding domain containing proteins in the IkB kinase (IKK) 31 and TAK1 kinase complexes [32][33][34] thus facilitating TAK-1-mediated phosphorylation and activation of IKKs. The latter subsequently phosphorylate the IkB proteins, which normally sequester NFkB in an inactive state in the cytoplasm, resulting in ubiquitination and proteasomal degradation of IkB and allowing for nuclear translocation of the liberated NFkB.…”

The Pellino family: IRAK E3 ligases with emerging roles in innate immune signalling

“…In this process, TRAF6 interacts with the E2 ubiquitin-conjugating heterodimer UbcH13-Uev1a, resulting in covalent attachment of Lys63-linked polyubiquitin chains to TRAF6 [12]. The IRAK1-TRAF6 complex interacts with another membrane complex consisting of TAK1 and its pre-associated proteins, TAK1-binding protein (TAB)1, TAB2 and TAB3 [13,14], through the recognition of polyubiquitin chains on TRAF6 by highly conserved zinc finger domains in TAB2 and TAB3 [15] (Figure 2). Other reports indicate that TAB2 can interact with unmodified TRAF6 [16] and facilitate its ubiquitylation [17].…”

“…Other reports indicate that TAB2 can interact with unmodified TRAF6 [16] and facilitate its ubiquitylation [17]. TAK1 and TAB2 are subsequently phosphorylated as part of the membrane complex and this is followed by translocation of a putative TRAF6-TAK1-TAB1-TAB2-TAB3 complex to the cytosol, at which TAK1 becomes activated by polyubiquitylated TRAF6 [10,13]. By contrast, IRAK1 remains in the membrane and is subsequently degraded with kinetics that vary with different TLR stimuli [10,18,19].…”