A Conserved Function in Phosphatidylinositol Metabolism for Mammalian Vps13 Family Proteins

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.

Yeast and other lower eukaryotic organisms for studies of Vps13 proteins in health and disease

“…Actin filament, microtubule and intermediate filament (desmin and cytokeratin) networks are all affected . It also regulates vesicular transport, autophagy and is involved in the metabolism of phosphoinositides (PIPs) . The hVps13B protein is a peripheral membrane protein localized to the Golgi complex, is required for maintenance of the Golgi complex morphology and is essential for the normal glycosylation of proteins .…”

“…27 It also regulates vesicular transport, 22,28 autophagy 29 and is involved in the metabolism of phosphoinositides (PIPs). 30 The hVps13B protein is a peripheral membrane protein localized to the Golgi complex, is required for maintenance of the Golgi complex morphology 31 and is essential for the normal glycosylation of proteins. 32 The hVps13C protein is enriched in the outer membrane of mitochondria, 8 lipid droplets 33 and, based on cell fractionation studies, in early endosomes.…”

Differential requirement for ATG2A domains for localization to autophagic membranes and lipid droplets

“…Additionally, these regions show high homology with the N-and C-terminal regions in VPS13 family proteins [17][18][19]. Previous reports suggested that human VPS13A regulates autophagy [18] and maintains the amount of phosphatidylinositol phosphates in the Golgi and the plasma membrane [20]. In yeast, Vps13 has membrane-binding activity [21] and functions at membrane contact sites [22][23][24].…”

Białka z rodziny Vps13 – od funkcji molekularnej do patogenezy chorób neurodegeneracyjnych

“…Innym efektem powiązanym z ograniczeniem aktywności kinazy PI3K w fibroblastach pacjentów z ChAc jest spadek poziomu białka Ora1, podjednostki kanału transportującego Ca 2+ do wnętrza komórki i zmniejszony napływ jonów Ca 2+ [43,44]. Zmiany w aktywności kinazy PI3K są duże, jednakże wyciszenie VPS13A w szczurzych komórkach PC12 nie zmienia znacząco poziomu PI(3,4,5)P 3 w błonie komórkowej, zaobserwowano natomiast znaczący spadek poziomu PI(4)P [45]. Inną kinazą, której aktywność jest zmieniona u pacjentów z ChAc jest kinaza Lyn, z rodziny kinaz Src.…”

“…lipidów. Stwierdzono, że mutant vps13∆ wykazuje zmniejszony poziom PI(4)P w błonach tworzących się spor, a w komórkach szczurzych PC12 pozbawionych genu VPS13A poziom PI(4)P jest obniżony w błonie komórkowej i w błonach aparatu Golgiego [45]. Sugeruje to, że Vps13 mógłby transportować PI(4)P lub jego prekursor PI.…”