Abstract
The Vps13 protein family is highly conserved in eukaryotic cells. In humans, mutations in the gene encoding the family member VPS13A lead to the neurodegenerative disorder chorea-acanthocytosis. In the yeast Saccharomyces cerevisiae, there is just a single version of VPS13, thereby simplifying the task of unraveling its molecular function(s). While VPS13 was originally identified in yeast by its role in vacuolar sorting, recent studies have revealed a completely different function for VPS13 in sporulation, where VPS13 regulates phosphatidylinositol-4-phosphate (PtdIns(4)P) levels in the prospore membrane. This discovery raises the possibility that the disease phenotype associated with vps13A mutants in humans is due to misregulation of PtdIns(4)P in membranes. To determine whether VPS13A affects PtdIns(4)P in membranes from mammalian neuronal cells, phosphatidylinositol phosphate pools were compared in PC12 tissue culture cells in the absence or presence of VPS13A. Consistent with the yeast results, the localization of PtdIns(4)P is specifically altered in VPS13A knockdown cells while other phosphatidylinositol phosphates appear unaffected. In addition, VPS13A is necessary to prevent the premature degeneration of neurites that develop in response to Nerve Growth Factor. The regulation of PtdIns(4)P is therefore a conserved function of the Vps13 family and may play a role in the maintenance of neuronal processes in mammals.
Highlights
Saccharomyces cerevisiae VPS13 is the founding member of a protein family that is highly conserved in eukaryotic cells[1]
VPS13A is required to prevent the premature degeneration of elongating neurites. These results suggest that regulation of PtdIns(4)P is a conserved function of Vps13 family proteins and provide potential insight into the basis for neuronal degeneration seen in ChAc
PC12 cells were first transfected with plasmids expressing GFP reporters that act as biosensors for either PtdIns(4)P (GFP-OSBP-pleckstrin homology (PH)), PtdIns(4,5)P2 (PLCδ1-PH-GFP), or PtdIns(3,4,5)P3 (Akt-PH-GFP)[24,25]
Summary
Saccharomyces cerevisiae VPS13 is the founding member of a protein family that is highly conserved in eukaryotic cells[1]. VPS13 was originally identified by the failure of vps mutant cells to deliver a lumenal protease to the vacuole (the yeast lysosome) [2]. This defect appears to be a secondary consequence of the failure of vps mutants to properly recycle. A Conserved Function of Vps sorting receptors from the endosome to the Golgi complex [3]. In addition to this role in vesicle transport, VPS13 has a second function in the process of sporulation [4,5,6]
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