Lysine 63-linked Polyubiquitination of TAK1 at Lysine 158 Is Required for Tumor Necrosis Factor α- and Interleukin-1β-induced IKK/NF-κB and JNK/AP-1 Activation

Abstract

Transforming growth factor-␤-activated kinase 1 (TAK1) plays an essential role in the tumor necrosis factor ␣ (TNF␣)-and interleukin-1␤ (IL-1␤)-induced IB kinase (IKK)/nuclear factor-B (NF-B) and c-Jun N-terminal kinase (JNK)/Tumor necrosis factor ␣ (TNF␣) 3 and interleukin-1␤ (IL-1␤) are two potent proinflammatory cytokines that play important roles in the regulation of immunity, inflammation, cell proliferation, differentiation, and apoptosis (1, 2). Cellular responses to TNF␣ and IL-1␤ are mediated by intracellular signaling pathways that control the activation of nuclear factor-B (NF-B) and activator protein 1 (AP-1) (3, 4).Upon binding to its receptor, TNF␣ induces formation of a receptor-associated complex, including the adaptor proteins TRADD, TRAF2, TRAF5, and RIP1, which subsequently leads to Lys 63 -linked polyubiquitination of TRAF2 and RIP1 (5-7). In contrast, IL-1␤ binding to its receptor induces a receptor-associated complex formation, including MyD88, IRAK1, IRAK4, and TRAF6, which is followed by Lys 63 -linked polyubiquitination of TRAF6 and IRAKs (8 -12). The formation of TRAF2-RIP1 and TRAF6-IRAK4 complexes as well as the Lys 63 -linked polyubiquitination of RIP1 and TRAF6 appear to enable the recruitment and activation of transforming growth factor-␤-activated kinase 1 (TAK1) through binding of the TAK1 regulatory subunits TAB2 and TAB3 to the Lys 63 -polyubiquitinated RIP1 and TRAF6. The activated TAK1 then triggers the activation of the IB kinase (IKK), c-Jun N-terminal kinase (JNK), and p38 MAPK (8,(13)(14)(15)(16)(17), which leads to activation of transcription factors NF-B and AP-1 and up-regulation of many genes encoding proinflammatory cytokines, chemokines, adhesion molecules, and proteolytic enzymes (18).The IKK complex consists of three subunits: two catalytic subunits, IKK␣ and IKK␤, and an essential regulatory subunit, IKK␥/NF-B essential modulator (NEMO) (3,19). Genetic studies have implicated that IKK␤ and IKK␥/NEMO are essential for the TNF␣-and IL-1␤-mediated . Phosphorylation of serine 177 and 181 residues in the activation loop is required for IKK␤ activation (23). IKK␥/NEMO has been indicated to bind Lys 63 -linked polyubiquitin chains (7,16,24,25). It is proposed that Lys 63 -polyubiquitin chains act as a scaffold to allow for assembly of a signaling complex that leads to IKK␤ activation. Once activated, IKK␤ phosphorylates IB proteins and leads to IB polyubiquitination with a Lys 48 -linked ubiquitin chain. Polyubiquitination-mediated degradation of IBs allows NF-B to translocate into the nucleus and activate NF-B-dependent gene expression (26).JNKs are members of three related mitogen-activated protein kinases (MAPKs), including the extracellular signal-regulated kinases (ERKs), JNKs, and p38 MAPKs (4, 27). JNKs and p38 MAPKs are involved in transmitting intracellular signals in

RETRACTED: Minocycline Targets the NF-κB Nexus through Suppression of TGF-β1-TAK1-IκB Signaling in Ovarian Cancer

“…Numerous kinases have been linked with the activation of IKK. Accumulating evidence suggests that the well-characterized MAP3K family member TAK1 is the central IKK kinase induced by several stimuli (31)(32)(33). Here, we found that minocycline inhibits TAK1 phosphorylation.…”

SASH1 Is a Scaffold Molecule in Endothelial TLR4 Signaling

“…TAK1 polyubiquitination has been shown to be essential for TAK1-mediated activation of IKK/NF-kB downstream of receptors for TNF and IL-1 (35). We have shown that SASH1 interacts with TAK1, and thus we wanted to determine whether SASH1 could regulate ubiquitination of TAK1.…”

Molecular Biology of Atherosclerosis

“…Thus adapters TAK1-binding protein 2 (TAB2) and NEMO bind the growing K63 chains bringing the IKK complex (NEMO, IKK1, and IKK2) into juxtaposition with active TAK1. Additional ubiquitination of TAK1 and NEMO seems to increase TAK1 activity and amplify the signal (498 Not shown in FIGURE 4 following TNFR1 activation is the more delayed or alternative formation of complex II which contains TRADD, RIP1, Fas-associated death domain (FADD), and pro-caspase 8. Activation of caspase 8 leads to caspase 3 activation and apoptosis.…”