VPS13B/COH1 is the only known causative factor for Cohen syndrome, an early-onset autosomal recessive developmental disorder with intellectual inability, developmental delay, joint hypermobility, myopia, and facial dysmorphism as common features, but the molecular basis of VPS13B/COH1 in pathogenesis remains largely unclear. Here, we identify Sec23 interacting protein (Sec23IP) at the ER exit site (ERES) as a VPS13B adaptor that recruits VPS13B to ERES-Golgi interfaces. VPS13B interacts directly with Sec23IP via the VPS13 adaptor binding domain (VAB), and the interaction promotes the association between ERES and the Golgi. Disease-associated missense mutations of VPS13B-VAB impair the interaction with Sec23IP. Knockout of VPS13B or Sec23IP blocks the formation of tubular ERGIC, an unconventional cargo carrier that expedites ER-to-Golgi transport. In addition, depletion of VPS13B or Sec23IP delays ER export of procollagen, suggesting a link between procollagen secretion and joint laxity in patients with Cohen disease. Together, our study reveals a crucial role of VPS13B-Sec23IP interaction at the ERES-Golgi interface in the pathogenesis of Cohen syndrome.

中文翻译：

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Sec23IP 将 VPS13B/COH1 募集到 ER 出口位点-高尔基体界面，用于管状 ERGIC 形成。


VPS13B/COH1 是 Cohen 综合征唯一已知的致病因素，Cohen 综合征是一种早发性常染色体隐性发育障碍，常见特征为智力障碍、发育迟缓、关节过度活动、近视和面部畸形，但 VPS13B/COH1 在发病机制中的分子基础在很大程度上仍不清楚。在这里，我们在 ER 出口位点 （ERES） 鉴定出 Sec23 相互作用蛋白 （Sec23IP） 作为将 VPS13B 募集到 ERES-高尔基体界面的 VPS13B 接头蛋白。VPS13B 通过 VPS13 接头结合域 （VAB） 直接与 Sec23IP 交互，这种相互作用促进了 ERES 和高尔基体之间的关联。VPS13B-VAB 的疾病相关错义突变会损害与 Sec23IP 的相互作用。VPS13B 或 Sec23IP 的敲除可阻止管状 ERGIC 的形成，ERGIC 是一种非常规货物载体，可加快 ER 到高尔基体的运输。此外，VPS13B 或 Sec23IP 的耗竭延迟了前胶原的 ER 输出，表明 Cohen 病患者的前胶原分泌与关节松弛之间存在联系。总之，我们的研究揭示了 ERES-高尔基体界面处 VPS13B-Sec23IP 相互作用在 Cohen 综合征发病机制中的关键作用。