State Key Laboratory of Protein and Plant Gene Research, LSC, Peking University, Beijing, China.
Mol Cell Biol. 2012 Oct;32(19):3990-4000. doi: 10.1128/MCB.00722-12. Epub 2012 Jul 30.
Interleukin-1 (IL-1) receptor-associated kinase (IRAK1) is phosphorylated, ubiquitinated, and degraded upon IL-1 stimulation. IRAK1 can be ubiquitinated through both K48- and K63-linked polyubiquitin chains upon IL-1 stimulation. While the Pellino proteins have been shown to meditate K63-linked polyubiquitination on IRAK1, the E3 ligase for K48-linked ubiquitination of IRAK1 has not been identified. In this study, we report that the SCF (Skp1-Cullin1-F-box)-β-TrCP complex functions as the K48-linked ubiquitination E3 ligase for IRAK1. IL-1 stimulation induced the interaction of IRAK1 with Cullin1 and β-TrCP. Knockdown of β-TrCP1 and β-TrCP2 attenuated the K48-linked ubiquitination and degradation of IRAK1. Importantly, β-TrCP deficiency abolished the translocation TAK1-TRAF6 complex from the membrane to the cytosol, resulting in a diminishment of the IL-1-induced TAK1-dependent pathway. Taken together, these results implicate a positive role of β-TrCP-mediated IRAK1 degradation in IL-1-induced TAK1 activation.
白细胞介素-1（IL-1）受体相关激酶（IRAK1）在受到 IL-1 刺激后会发生磷酸化、泛素化和降解。在受到 IL-1 刺激后，IRAK1 可以通过 K48 和 K63 连接的多泛素链进行泛素化。虽然已经表明 Pellino 蛋白介导 IRAK1 上的 K63 连接多泛素化，但 IRAK1 的 K48 连接泛素化的 E3 连接酶尚未被鉴定。在这项研究中，我们报告说，SCF（Skp1-Cullin1-F-box）-β-TrCP 复合物是 IRAK1 的 K48 连接泛素化 E3 连接酶。IL-1 刺激诱导 IRAK1 与 Cullin1 和 β-TrCP 的相互作用。β-TrCP1 和 β-TrCP2 的敲低减弱了 IRAK1 的 K48 连接泛素化和降解。重要的是，β-TrCP 缺陷消除了 TAK1-TRAF6 复合物从膜向细胞质的易位，导致 IL-1 诱导的 TAK1 依赖性途径减弱。总之，这些结果表明，β-TrCP 介导的 IRAK1 降解在 IL-1 诱导的 TAK1 激活中起积极作用。
