SHIP164 is a chorein motif lipid transfer protein that controls endosome–Golgi membrane traffic

Abstract

Cellular membranes differ in protein and lipid composition as well as in the protein–lipid ratio. Thus, progression of membranous organelles along traffic routes requires mechanisms to control bilayer lipid chemistry and their abundance relative to proteins. The recent structural and functional characterization of VPS13-family proteins has suggested a mechanism through which lipids can be transferred in bulk from one membrane to another at membrane contact sites, and thus independently of vesicular traffic. Here, we show that SHIP164 (UHRF1BP1L) shares structural and lipid transfer properties with these proteins and is localized on a subpopulation of vesicle clusters in the early endocytic pathway whose membrane cargo includes the cation-independent mannose-6-phosphate receptor (MPR). Loss of SHIP164 disrupts retrograde traffic of these organelles to the Golgi complex. Our findings raise the possibility that bulk transfer of lipids to endocytic membranes may play a role in their traffic.

In silico modelling human VPS13 proteins associated with donor and target membranes suggests lipid transfer mechanisms

“…1). These proteins appear to bind and transfer phosphatidylcholines and phosphatidylethanolamines (Kumar et al, 2018;Hanna et al, 2022) across intermembrane bridges formed by the RBG repeats, which is in line with our structure prediction models, where the highly hydrophobic inner channel of the RBG domains has an internal diameter of 4-6 nm that may accommodate several lipids at once (Fig. 1).…”

“…In addition to another group of structured domains that we collectively called SGDs ( Video 1 ), which appear closely related between VPS13A and VPS13C (Kumar et al, 2018), we found several conserved helical structures at the edges of the seam of the VPS13 proteins, potentially suggesting that these are embedded in a network of interactors which extends over the intramembrane bridge. Most curiously, such an architectural geometry characterised by RBG repeats and their laterally connected cytosolic loops appears to be a common feature of the RBG protein superfamily, especially in ATG2, Hob and SHIP164 (Hanna et al, 2022; Neuman et al, 2022).…”

“…It is currently unknown how lipids are transported across RBG protein-formed bridges, if this transport is directional, and how this transport may be regulated. Recent studies show that directionality of transport is not necessarily an innate feature of all RBG domain-containing proteins, as SHIP164 forms a tail-to-tail dimer, where the Chorein domain is most likely embedded in both donor and target membranes (Hanna et al, 2022), and lipid transfer via SHIP164 appears to be between similar donor and target organelles. However, VPS13/ATG2 proteins span junctions between dissimilar organelles.…”

“…The copyright holder for this preprint (which this version posted July 29, 2022. ; https://doi.org/10.1101/2022.07.27.501698 doi: bioRxiv preprint potentially suggesting that these are embedded in a network of interactors which extends over the intramembrane bridge. Most curiously, such an architectural geometry characterised by RBG repeats and their laterally connected cytosolic loops appears to be a common feature of the RBG protein superfamily, especially in ATG2, Hob and SHIP164 (Hanna et al, 2022;Neuman et al, 2022).…”

A complex containing RhoBTB3-SHIP164-Vps26B promotes the biogenesis of early endosome buds at Golgi-endosome contacts

“…Vps13/Chorein domain at its NT, homologous with Vps13 proteins, indicating that SHIP164 is another bridge lipid transporter that is implicated in endosomes to Golgi trafficking 31 .…”