Retrograde transport of WLS (Wntless) from endosomes to trans-Golgi network (TGN) is required for efficient Wnt secretion during development. However, the molecular players connecting endosomes to TGN during WLS trafficking are limited. Here, we identified a role for Eyes Absent (EYA) proteins during retrograde trafficking of WLS to TGN in human cell lines. By using worm, fly, and zebrafish models, we found that the EYA-secretory carrier-associated membrane protein 3 (SCAMP3) axis is evolved in vertebrates. EYAs form a complex and interact with retromer on early endosomes. Retromer-bound EYA complex recruits SCAMP3 to endosomes, which is necessary for the fusion of WLS-containing endosomes to TGN. Loss of EYA complex or SCAMP3 leads to defective transport of WLS to TGN and failed Wnt secretion. EYA mutations found in patients with hearing loss form a dysfunctional EYA-retromer complex that fails to activate Wnt signaling. These findings identify the EYA complex as a component of retrograde trafficking of WLS from the endosome to TGN.

中文翻译：

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EYA 蛋白复合物是 Wntless 从内体逆行运输到高尔基体所必需的


WLS （Wntless） 从内体逆向转运到反式高尔基体网络 （TGN） 是发育过程中有效分泌 Wnt 所必需的。然而，在 WLS 运输过程中将内体连接到 TGN 的分子参与者是有限的。在这里，我们确定了 Eyes Absence （EYA） 蛋白在人类细胞系中 WLS 逆行运输到 TGN 中的作用。通过使用蠕虫、苍蝇和斑马鱼模型，我们发现 EYA 分泌型载体相关膜蛋白 3 （SCAMP3） 轴在脊椎动物中进化。EYA 形成复合物并与早期内体上的逆转录异体相互作用。逆转录酶结合的 EYA 复合物将 SCAMP3 募集到内体，这是含 WLS 的内体与 TGN 融合所必需的。EYA 复合物或 SCAMP3 的缺失导致 WLS 向 TGN 的转运缺陷和 Wnt 分泌失败。在听力损失患者中发现的 EYA 突变形成功能失调的 EYA-逆转录酶复合物，无法激活 Wnt 信号传导。这些发现确定 EYA 复合物是 WLS 从内体逆行运输到 TGN 的组成部分。