TLR4 复合物内 TRAF6 介导的 TAK1 复合物诱导
中文名称
通路描述
在人类中，与泛素结合 E2 型酶 UBC13 和 UEV1A (也称为 UBE2V1) 一起，TRAF6 催化 Lys63 连接泛素化。人们相信 TRAF6 的自多泛素化和寡聚化后，与 TAB2 或 TAB3 (TAK1 结合蛋白 2 和 3) 的泛素受体结合，从而刺激 TGF beta-activated kinase 1(TAK1) 的磷酸化和激活。TAK1 磷酸化 IKK alpha 和 IKK beta，进而磷酸化 NF-kB 抑制物 - IkB，最终导致 IkB 降解和 NF-kB 转位至细胞核。此外，TAK1 通过磷酸化 MKK4/7 和 MKK3/6 分别介导 JNK 和 p38 MAP 激酶的激活，从而激活许多转录因子。TRAF6 的作用存在争议，并且可能因细胞类型而异。TRAF6 自泛素化被发现对 TRAF6 激活 TAK1 通路是必需的。这些发现与 Xia et al. (2009) 提出的 TRAF6 介导 NF-kB 激活的新机制一致。TRAF6 产生未锚定的 Lys63 连接多泛素链，与 TAK1 (TAB2 或 TAB3) 和 IKK(NEMO) 的调节亚基结合，导致激酶的激活。 Xia et al. (2009) 体外研究表明，与共价连接到 TRAF6 或 IRAK 的多泛素链不同，TAB2 和 NEMO 关联的泛素链被发现是未锚定的，并且易受 N 端泛素切割。只有 K63 连接的多泛素链，而不是单体泛素，以剂量依赖性方式激活 TAK1。使用包含 K48 和 K63 连接的泛素聚合物实现了 IKK 复合物最佳激活。此外，作者提出，TAK1 复合物可能通过结合几个 TAB2/3 到单个多泛素链上，以接近促进 TAK1 激酶跨磷酸化。或者，应考虑多 Ub 结合促进 TAK1 复合物变构激活的可能性 (Walsh et al 2008)。
英文描述
TRAF6-mediated induction of TAK1 complex within TLR4 complex In human, together with ubiquitin-conjugating E2-type enzymes UBC13 and UEV1A (also known as UBE2V1), TRAF6 catalyses Lys63-linked ubiquitination. It is believed that auto polyubiquitination and oligomerization of TRAF6 is followed by binding the ubiquitin receptors of TAB2 or TAB3 (TAK1 binding protein 2 and 3), which stimulates phosphorylation and activation of TGF beta-activated kinase 1(TAK1).TAK1 phosphorylates IKK alpha and IKK beta, which in turn phosphorylate NF-kB inhibitors - IkB and eventually results in IkB degradation and NF-kB translocation to the nucleus. Also TAK1 mediates JNK and p38 MAP kinases activation by phosphorylating MKK4/7 and MKK3/6 respectivly resulting in the activation of many transcription factors. The role of TRAF6 is somewhat controversial and probably cell type specific. TRAF6 autoubiquitination was found to be dispensable for TRAF6 function to activate TAK1 pathway. These findings are consistent with the new mechanism of TRAF6-mediated NF-kB activation that was suggested by Xia et al. (2009). TRAF6 generates unanchored Lys63-linked polyubiquitin chains that bind to the regulatory subunits of TAK1 (TAB2 or TAB3) and IKK(NEMO), leading to the activation of the kinases. Xia et al. (2009) demonstrated in vitro that unlike polyubiquitin chains covalently attached to TRAF6 or IRAK, TAB2 and NEMO-associated ubiquitin chains were found to be unanchored and susceptible to N-terminal ubiquitin cleavage. Only K63-linked polyubiquitin chains, but not monomeric ubiquitin, activated TAK1 in a dose-dependent manner. Optimal activation of the IKK complex was achieved using ubiquitin polymers containing both K48 and K63 linkages.Furthermore, the authors proposed that the TAK1 complexes might be brougt in close proximity by binding several TAB2/3 to a single polyubiquitin chain to facilitate TAK1 kinase trans-phosphorylation. Alternativly, the possibility that polyUb binding promotes allosteric activation of TAK1 complex should be considered (Walsh et al 2008).
所含基因
14 个基因