Lautenberg Centre for Immunology and Cancer Research, Institute for Medical Research Israel-Canada, The Hebrew University, Hadassah Medical School, Jerusalem, Israel.
Immunol Rev. 2012 Mar;246(1):77-94. doi: 10.1111/j.1600-065X.2012.01098.x.
The nuclear factor-κB (NF-κB) signaling pathway is a busy ground for the action of the ubiquitin-proteasome system; many of the signaling steps are coordinated by protein ubiquitination. The end point of this pathway is to induce transcription, and to this end, there is a need to overcome a major obstacle, a set of inhibitors (IκBs) that bind NF-κB and prohibit either the nuclear entry or the DNA binding of the transcription factor. Two major signaling steps are required for the elimination of the inhibitors: activation of the IκB kinase (IKK) and degradation of the phosphorylated inhibitors. IKK activation and IκB degradation involve different ubiquitination modes; the latter is mediated by a specific E3 ubiquitin ligase SCF(β-TrCP) . The F-box component of this E3, β-TrCP, recognizes the IκB degron formed following phosphorylation by IKK and thus couples IκB phosphorylation to ubiquitination. SCF(β-TrCP) -mediated IκB ubiquitination and degradation is a very efficient process, often resulting in complete degradation of the key inhibitor IκBα within a few minutes of cell stimulation. In vivo ablation of β-TrCP results in accumulation of all the IκBs and complete NF-κB inhibition. As many details of IκB-β-TrCP interaction have been worked out, the development of β-TrCP inhibitors might be a feasible therapeutic approach for NF-κB-associated human disease. However, we may still need to advance our understanding of the mechanism of IκB degradation as well as of the diverse functions of β-TrCP in vivo.
核因子-κB（NF-κB）信号通路是泛素-蛋白酶体系统作用的活跃场所；许多信号步骤都通过蛋白质泛素化来协调。该通路的终点是诱导转录，为此，需要克服一个主要障碍，即一组与 NF-κB 结合并阻止转录因子核内进入或 DNA 结合的抑制剂（IκBs）。消除抑制剂需要两个主要的信号步骤：IκB 激酶（IKK）的激活和磷酸化抑制剂的降解。IKK 激活和 IκB 降解涉及不同的泛素化模式；后者由特定的 E3 泛素连接酶 SCF（β-TrCP）介导。这种 E3 的 F-box 成分β-TrCP 识别 IKK 磷酸化后形成的 IκB 降解基序，从而将 IκB 磷酸化与泛素化偶联。SCF（β-TrCP）介导的 IκB 泛素化和降解是一个非常有效的过程，通常在细胞刺激后几分钟内导致关键抑制剂 IκBα的完全降解。体内敲除β-TrCP 会导致所有 IκBs 的积累和 NF-κB 的完全抑制。由于 IκB-β-TrCP 相互作用的许多细节已经被阐明，因此开发β-TrCP 抑制剂可能是治疗与 NF-κB 相关的人类疾病的可行方法。然而，我们可能仍然需要深入了解 IκB 降解的机制以及β-TrCP 在体内的多种功能。
