VPS13B is localized at the cis-trans Golgi complex interface and is a functional partner of FAM177A1

Abstract

Mutations in VPS13B, a member of a protein family implicated in bulk lipid transport between adjacent membranes, cause Cohen syndrome. VPS13B is known to be concentrated in the Golgi complex, but its precise location within this organelle and thus the site(s) where it achieves lipid transport remains unclear. Here we show that VPS13B is localized at the interface between cis and trans Golgi sub-compartments and that Golgi complex re-formation after Brefeldin A (BFA) induced disruption is delayed inVPS13BKO cells. This delay is phenocopied by loss of FAM177A1, a Golgi complex protein of unknown function reported to be a VPS13B interactor and whose mutations also result in a developmental disorder. In zebrafish, thevps13borthologue, not previously annotated in this organism, genetically interacts withfam177a1. Collectively, these findings raise the possibility that bulk lipid transport by VPS13B may play a role in expanding Golgi membranes and that VPS13B may be assisted in this function by FAM177A1.

Exploring the pathological mechanisms underlying Cohen syndrome

“…This finding implies a potential role in Golgi retrograde trafficking, although establishing a cause-and-effect relationship would require further investigations. The observation of Ugur et al (2023) of a potential cis-to-trans Golgi bridging function of VPS13B aligns with this hypothesis. So far, the better-established inter-Golgi retrograde traffic mechanism is vesicle-mediated and is orchestrated by the Conserved Oligomeric Golgi (COG) complex in cooperation of set of Golgi SNARE proteins.…”

“…Interestingly, silencing RAB6, a VPS13B interactor, was found to partially prevent localization of VPS13B to the Golgi, highlighting its potential role in Golgi association ( Seifert et al, 2015 ). Although it remains unclear whether VPS13B establishes connections between the Golgi and other organelles, immunofluorescence after hypotonic-mediated organelle swelling, indicates that VPS13B may localize at the interface between cis- and trans-Golgi membranes, potentially forming MCS between different Golgi cisternae ( Ugur et al, 2023 ). VPS13B has also been found in association with lipid droplets, particularly in a subset of lipid droplets in close contact with the Golgi ( Du et al, 2023 ; Figure 1 ).…”

“…Moreover, Family With Sequence Similarity 177 Member A (FAM177A), a Golgi-localized protein of unknown function, has been proposed as a functional interactor of VPS13B. FAM177A is linked to a neurodevelopmental genetic disorder with phenotypic similarities to CS and exhibits a cellular phenotype similar to that of VPS13B ( Ugur et al, 2023 ).…”