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.

An evolving understanding of sorting signals for endosomal retrieval

“…Although the SNX4 complex is conserved in mammals, it remains to be determined whether mammalian SNX4 complex has a similar function. A more recent study further identifies that Mvp1p mediates another endosomal recycling pathway, independent of retromer and Snx4p (Suzuki et al, 2021). Mvp1p binds to endosomal membrane protein Vps55p via its ''YXTXXFM'' motif and is responsible for Vps55p delivery to the Golgi (Suzuki et al, 2021).…”

“…A more recent study further identifies that Mvp1p mediates another endosomal recycling pathway, independent of retromer and Snx4p (Suzuki et al, 2021). Mvp1p binds to endosomal membrane protein Vps55p via its ''YXTXXFM'' motif and is responsible for Vps55p delivery to the Golgi (Suzuki et al, 2021). The sorting motif recognized by Mvp1p is distinct from those of retromer and Snx4p.SNX8, the mammalian homolog of Mvp1p, could mediate the formation of endosomal tubules.…”

“…SNX4 (Snx4p in yeast) and SNX8 (Mvp1p in yeast) are members of the SNX-BAR subfamily. Both genes are involved in retromer-independent membrane trafficking in yeast (Suzuki and Emr, 2018;Suzuki et al, 2021). Snx4p forms a complex with either Snx41p or Snx42p and is required for the vacuole-to-endosome recycling of autophagy protein Atg27p (Suzuki and Emr, 2018).…”

Crystal structure of the PX domain of Vps17p from Saccharomyces cerevisiae

“…Recycling of receptors and transporters from the endosomes to the Golgi compartment is essential for the assembly and function of the lysosome (Cullen, 2008). Saccharomyces cerevisiae (baker's yeast) has three major endosomal recycling pathways: retromer, Snx4 and Mvp1/Snx8 (Suzuki et al, 2021). The principal components of the three pathways are SNX-BAR proteins (van Weering et al, 2010;Yong et al, 2020).…”

“…The BAR domain functions to induce and stabilize membrane curvature. S. cerevisiae has at least 15 PX domain-containing proteins (Yu & Lemmon, 2001), including seven SNX-BAR proteins (Suzuki et al, 2021). Among them, Vps17p (vacuolar protein sorting-associated protein 17) functions in membrane binding/deformation as the SNX-BAR protein subunit of the membrane-associated retromer complex (Seaman & Williams, 2002).…”