The TAK1–TRAF6 signalling pathway

Antiviral TRIMs: friend or foe in autoimmune and autoinflammatory disease?

“…For both the TLR and RLR pathways the common convergence point in the activation of NFκB is the E3 ligase TRAF6. Autoubiquitination of TRAF6 results in recruitment of the adaptor proteins TAB2 and TAB3 and the kinase TAK1, resulting in activation of IKKs ( [58] and reviewed in [59,60]). Highlighting the importance of the TAB1/TAK1 in regulating NFκB activation, TRIM5α and its murine orthologue TRIM30 have been shown to interact with, ubiquitinate and degrade TAB2 and TAB3, resulting in disruption of the TRAF6/TAK1/TAB complex and inactivation of NFκB dependent pathways ( [61,62]).…”

Poxviral Protein A52 Stimulates p38 Mitogen-activated Protein Kinase (MAPK) Activation by Causing Tumor Necrosis Factor Receptor-associated Factor 6 (TRAF6) Self-association Leading to Transforming Growth Factor β-activated Kinase 1 (TAK1) Recruitment

“…For IL-1 and TLR signaling, TRAF6 is required for activation of both p38 and NFB (30). The generation of Lys-63-linked polyubiquitin chains associated with a TRAF6 complex and likely generated by the E3 ligase activity of TRAF6, is essential for downstream signaling (20,24). The TAK1-associated protein TAB2 binds to Lys-63-linked polyubiquitin chains, resulting in autophosphorylation of TAK1 at Ser-187 and its subsequent activation (41).…”

“…Similar to many viral immunomodulatory proteins, A52 has more than one function, and as well as exerting an inhibitory effect on IL-1R/TLR-mediated NFB activation, A52 activates p38 MAP kinase in an IRAK2-independent manner (16). The ability of A52 to activate p38 MAP kinase depends on TRAF6 (16), a protein also required by IL-1, TLRs, and TGF␤ for MAP kinase activation (20). A52-mediated p38 MAP kinase activation via cellular TRAF6 likely represents an immune subversion strategy whereby the virus gains a selective advantage by fine-tuning the signaling environment of an infected cell, for example to potentiate TLRinduced production of IL-10, a cytokine that inhibits inflammatory and cell-mediated immune responses and contributes to viral persistence (16).…”

“…TAK1 subsequently activates distinct pathways leading to NFB activation via the IB kinase (IKK) complex, and MAP kinase activation via a MAP kinase cascade. For p38 activation, TAK1 activates MKK3 and MKK6, which then phosphorylate p38 (20).…”

MAP3K7 and GSTZ1 are associated with human longevity: a two-stage case–control study using a multilocus genotyping

“…Various stressors and inflammatory cytokines trigger the activation of MAP3K7 which in turn activates key intracellular kinases such as the p38 MAPK, c-jun N-terminal kinase, and I-kappa B kinase complex. These pathways ultimately activate transcription factors nuclear factor-kappa B and activator protein-1 which are critical regulators of genes of the immune-inflammatory responses (Ninomiya-Tsuji et al 1999;Sato et al 2005;Chen et al 2006;Landström 2010). Studies have also demonstrated that the oxidative stress caused by reactive oxygen species (ROS) may induce or mediate the activation of the MAPK pathways, including the one mediated by MAP3K (Son et al 2011 for a review).…”