Ubiquitin-mediated activation of TAK1 and IKK

Abstract

Transforming growth factor b activated kinase-1 (TAK1), a member of the mitogen-activated protein kinase kinase kinase family, has emerged as a key regulator of signal transduction cascades leading to the activation of the transcription factors nuclear factor-kappa B (NF-jB) and activator protein-1 (AP-1). Stimulation of cells with cytokines and microbial pathogens results in the activation of TAK1, which subsequently activates the I-kappa B kinase complex (IKK) and mitogen-activated protein (MAP) kinases, culminating in the activation of NF-jB and AP-1, respectively. Recent studies have shown that polyubiquitination of signalling proteins through lysine (Lys)-63-linked polyubiquitin chains plays an important role in the activation of TAK1 and IKK. Unlike Lys-48-linked polyubiquitination, which normally targets proteins for degradation by the proteasome, Lys-63-linked polyubiquitin chains act as scaffolds to assemble protein kinase complexes and mediate their activation through proteasome-independent mechanisms. The concept of ubiquitin-mediated activation of protein kinases is supported by the discoveries of ubiquitination and deubiquitination enzymes as well as ubiquitin-binding proteins that function upstream of TAK1 and IKK. Recent biochemical and genetic studies provide further insights into the mechanism and function of ubiquitin signalling and these advances will be the focus of this review.

Salmonella Secreted Factor L Deubiquitinase of Salmonella typhimurium Inhibits NF-κB, Suppresses IκBα Ubiquitination and Modulates Innate Immune Responses

“…Ubiquitin contains seven lysine residues, but ubiquitin chains linked on Lys 48 and Lys 63 are the best characterized, to date. Whereas Lys 48 -linked polyubiquitin chains represent a signal for proteosomal degradation of modified substrates such as I B␣, Lys 63 -linked polyubiquitination acts as scaffolds to assemble signaling complexes and regulates protein localization, protein kinase activation, DNA repair, or transcription through proteasome-independent mechanisms (38,39). However, both Lys 48 -and Lys 63 -mediated ubiquitination play roles in regulating NF-B activity (10,35,38,40).…”

Adenosine A1 receptor regulates osteoclast formation by altering TRAF6/TAK1 signaling

“…In this process, TAK1-associated binding protein-2 (TAB2) acts as a bridge linking TRAF6 to TAK1 [26]. Although the mechanism by which TAK1 is activated is not fully understood, many studies have revealed the critical role of the lysine-63-linked polyubiquitination by TRAF6 in the activation of TAK1 [27,28].…”

TLR2 and TLR4 signaling pathways are required for recombinant Brucella abortus BCSP31-induced cytokine production, functional upregulation of mouse macrophages, and the Th1 immune response in vivo and in vitro

“…24,25 IRAK-1 in turn mediates the ubiquitination of TRAF6 and then activates TGF-b-activated kinase 1 (TAK1), which is required for NF-kB and mitogen-activated protein kinase (MAPK) activation induced by TLR ligands. 24,26 Activated TAK1 phosphorylates IkB kinase (IKK) and MAPK kinase 6, culminating in the degradation of the NF-kB inhibitor, IkBa, resulting in translocation of NF-kB to the nucleus where it regulates gene expression. 24,25,27 NF-kB, which is primarily composed of p50 and p65 proteins and retained in the cytoplasm by the inhibitory subunitIkBa, plays a role in inflammation and immune modulation.…”