Myddosome is an oligomeric complex required for the transmission of inflammatory signals from TLR/IL1Rs and consists of MyD88 and IRAK family kinases. However, the molecular basis for the self-assemble of Myddosome proteins and regulation of intracellular signaling remains poorly understood. Here, we identify OTUD5 acts as an essential regulator for MyD88 oligomerization and Myddosome formation. OTUD5 directly interacts with MyD88 and cleaves its K11-linked polyubiquitin chains at Lys95, Lys231 and Lys250. This polyubiquitin cleavage enhances MyD88 oligomerization after LPS stimulation, which subsequently promotes the recruitment of downstream IRAK4 and IRAK2 to form Myddosome and the activation of NF-κB and MAPK signaling and production of inflammatory cytokines. Consistently, Otud5-deficient mice are less susceptible to LPS- and CLP-induced sepsis. Taken together, our findings reveal a positive regulatory role of OTUD5 in MyD88 oligomerization and Myddosome formation, which provides new sights into the treatment of inflammatory diseases.

Myddosome 是传输 TLR/IL1R 炎症信号所需的寡聚复合物，由 MyD88 和 IRAK 家族激酶组成。然而，Myddosome 蛋白自组装和细胞内信号传导调节的分子基础仍然知之甚少。在这里，我们确定 OTUD5 是 MyD88 寡聚化和 Myddosome 形成的重要调节因子。 OTUD5 直接与 MyD88 相互作用，并在 Lys95、Lys231 和 Lys250 处裂解其 K11 连接的多聚泛素链。这种多泛素裂解增强了 LPS 刺激后 MyD88 寡聚化，随后促进下游 IRAK4 和 IRAK2 的募集以形成 Myddosome，并激活 NF-κB 和 MAPK 信号传导以及炎症细胞因子的产生。一致的是，Otud5 缺陷小鼠对 LPS 和 CLP 诱导的败血症不太敏感。总而言之，我们的研究结果揭示了 OTUD5 在 MyD88 寡聚化和 Myddosome 形成中的积极调节作用，这为炎症性疾病的治疗提供了新的视角。