A PX-BAR protein Mvp1/SNX8 and a dynamin-like GTPase Vps1 drive endosomal recycling

Abstract

Membrane protein recycling systems are essential for maintenance of the endosome-lysosome system. In yeast, retromer and Snx4 coat complexes are recruited to the endosomal surface where they recognize cargos. They sort cargo and deform the membrane into recycling tubules that bud from the endosome and target to the Golgi. Here, we reveal that the SNX-BAR protein, Mvp1, mediates an endosomal recycling pathway which is mechanistically distinct from the retromer and Snx4 pathways. Mvp1 deforms the endosomal membrane and sorts cargos containing a specific sorting motif into a membrane tubule. Subsequently, Mvp1 recruits the dynamin-like GTPase Vps1 to catalyze membrane scission and release of the recycling tubule. Similarly, SNX8, the human homolog of Mvp1, which has been also implicated in Alzheimer's disease, mediates formation of an endosomal recycling tubule. Thus, we present evidence for a novel endosomal retrieval pathway that is conserved from yeast to humans.

The VINE complex is a VPS9-domain GEF-containing SNX-BAR coat involved in endosomal sorting

“…In pre-WGD species, the single ancestral form of Vps5 must partner with both Vrl1 and Vps17, which requires some promiscuity in BAR-BAR pairing. This is consistent with our ab initio modeling, which predicted a variety of pairings between the PX-BAR domains of Vps5, Vps17, Vrl1 and Vin1, while the PX-BAR protein Mvp1 was predicted to form only homodimers, consistent with in vivo observations (Suzuki et al, 2021).…”

“…To assess the accuracy of ColabFold in predicting specific BAR domain pairings, we systematically modelled pairwise homotypic and heterotypic interactions of several yeast SNX-BAR proteins (Figure 3B, Table S3). This accurately predicted the homodimerization of Mvp1 (Suzuki et al, 2021) and the heterodimerization of Vps5/Vps17 (Seaman and Williams, 2002). Neither Vrl1 nor Vin1 were predicted to form homodimers, though unexpectedly Vrl1 was predicted to pair equally well with both Vin1 and its paralog Vps5.…”

“…We wondered if the VINE complex occupies endosomal membrane tubules as other SNX-BAR coat complexes do (Suzuki et al, 2021; van Weering et al, 2012; Zhang et al, 2021). To test this, we co-overexpressed Vrl1 and GFP-Vin1 on the strong ADH1 and NOP1 promoters, respectively, and acquired images of GFP-Vin1 at 100ms intervals (Figure 6A).…”

“…Our work suggests that VINE is a novel sorting complex that acts in a pathway-specific manner, thus joining the group of SNX-BAR complexes that promote independent sorting pathways from the endosome or vacuole in yeast (Ma and Burd, 2020; Suzuki et al, 2021). We identified the MPR-related protein Mrl1 as a candidate VINE cargo.…”

“…These SNX-BAR dimers, which are capable of deforming cargo-rich membranes into sorting tubules, are emerging as important regulators of protein transport. The seven SNX-BAR proteins present in yeast include the conserved retromer subunits Vps5 and Vps17 (Horazdovsky et al, 1997), the SNX8 homolog Mvp1 (Suzuki et al, 2021), the SNX4 homolog Snx4 and its partners Snx41 and Atg20 (SNX7 and SNX30 in humans, respectively; Hettema et al, 2003) and the Vps5 paralog Ykr078w. Retromer and Snx4 complexes promote cargo sorting from the endosome and vacuole (Arlt et al, 2015; Suzuki and Emr, 2018), while Mvp1 appears to function only at the endosome (Suzuki et al, 2021).…”