Sec23IP recruits the Cohen syndrome factor VPS13B/COH1 to ER exit site-Golgi interface for tubular ERGIC formation

Abstract 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 is unknown. Here, we identify Sec23 interacting protein (Sec23IP) at 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 ERES-Golgi interface in the pathogenesis of Cohen syndrome.