Interleukin-1 receptor-associated kinases (IRAKs) −4, −2, and −1 are involved in transducing signals from Toll-like receptors (TLRs) via the adaptor myeloid differentiation primary-response protein 88 (MYD88). How MYD88/IRAK4/2/1 complexes are formed, their redundancies, and potential non-enzymatic roles are subjects of debate. Here, we examine the hierarchical requirements for IRAK proteins in the context of TLR4 activation and confirmed that the kinase activity of IRAK4 is essential for MYD88 signaling. Surprisingly, the IRAK4 scaffold is required for activation of the E3 ubiquitin ligase TNF receptor-associated factor 6 (TRAF6) by both MYD88 and TIR domain-containing adaptor protein inducing IFN-β (TRIF), a unique adaptation in the TLR4 response. IRAK4 scaffold is, therefore, essential in integrating MYD88 and TRIF in TLR4 signaling.

白细胞介素 1 受体相关激酶 (IRAK) -4、-2 和 -1 参与通过接头骨髓分化初级反应蛋白 88 (MYD88) 转导来自 Toll 样受体 (TLR) 的信号。MYD88/IRAK4/2/1 复合物是如何形成的、它们的冗余性和潜在的非酶作用是争论的主题。在这里，我们在 TLR4 激活的背景下检查 IRAK 蛋白的层次要求，并证实 IRAK4 的激酶活性对 MYD88 信号传导至关重要。令人惊讶的是，通过 MYD88 和含有 TIR 结构域的衔接蛋白诱导 IFN-β (TRIF) 激活 E3 泛素连接酶 TNF 受体相关因子 6 (TRAF6) 需要 IRAK4 支架，这是 TLR4 反应中的一种独特适应。因此，IRAK4 支架对于将 MYD88 和 TRIF 整合到 TLR4 信号传导中至关重要。