The sorting of soluble secretory proteins from the endoplasmic reticulum (ER) to the Golgi complex is mediated by coat protein complex II (COPII) vesicles and thought to required specific ER membrane cargo-receptor proteins. However, these receptors remain largely unknown. Herein, we show that ER to Golgi transfer of vesicular cargo proteins requires WFS1, an ER-associated membrane protein whose loss of function leads to Wolfram syndrome. Mechanistically, WFS1 directly binds to vesicular cargo proteins including proinsulin via its ER luminal C-terminal segment, whereas pathogenic mutations within this region disrupt the interaction. The specific ER export signal encoded in the cytosolic N-terminal segment of WFS1 is recognized by the COPII subunit SEC24, generating mature COPII vesicles that traffic to the Golgi complex. WFS1 deficiency leads to abnormal accumulation of proinsulin in the ER, impeding the proinsulin processing as well as insulin secretion. This work identifies a vesicular cargo receptor for ER export and suggests that impaired peptide hormone transport underlies diabetes resulting from pathogenic WFS1 mutations.

可溶性分泌蛋白从内质网 (ER) 到高尔基复合体的分选由外壳蛋白复合体 II (COPII) 囊泡介导，并被认为需要特定的 ER 膜货物受体蛋白。然而，这些受体在很大程度上仍然未知。在此，我们表明囊泡货物蛋白的 ER 到高尔基体转移需要 WFS1，WFS1，一种 ER 相关的膜蛋白，其功能丧失导致 Wolfram 综合征。从机制上讲，WFS1 通过其内质网腔 C 端区段直接与囊泡货物蛋白（包括胰岛素原）结合，而该区域内的致病突变会破坏相互作用。在 WFS1 的胞质 N 末端片段中编码的特定 ER 输出信号被 COPII 亚基 SEC24 识别，生成成熟的 COPII 囊泡，然后运输到高尔基复合体。WFS1 缺乏导致 ER 中胰岛素原的异常积累，阻碍胰岛素原的加工以及胰岛素的分泌。这项工作确定了 ER 输出的囊泡货物受体，并表明肽激素转运受损是由致病性引起的糖尿病的基础。WFS1突变。