Genetic Dissection of Vps13 Regulation in Yeast Using Disease Mutations from Human Orthologs.

Jae-Sook Park,Nancy M Hollingsworth,Aaron M Neiman

doi:10.3390/ijms22126200

Jae-Sook Park, Nancy M Hollingsworth + Show 1 more

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https://doi.org/10.3390/ijms22126200

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Abstract

The VPS13 family of proteins have emerged as key players in intracellular lipid transport and human health. Humans have four different VPS13 orthologs, the dysfunction of which leads to different diseases. Yeast has a single VPS13 gene, which encodes a protein that localizes to multiple different membrane contact sites. The yeast vps13Δ mutant is pleiotropic, exhibiting defects in sporulation, protein trafficking, endoplasmic reticulum (ER)-phagy and mitochondrial function. Non-null alleles resulting from missense mutations can be useful reagents for understanding the multiple functions of a gene. The exceptionally large size of Vps13 makes the identification of key residues challenging. As a means to identify critical residues in yeast Vps13, amino acid substitution mutations from VPS13A, B, C and D, associated with human disease, were introduced at the cognate positions of yeast VPS13, some of which created separation-of-function alleles. Phenotypic analyses of these mutants have revealed that the promotion of ER-phagy is a fourth, genetically separable role of VPS13 and provide evidence that co-adaptors at the endosome mediate the activity of VPS13 in vacuolar sorting.

Highlights

The VPS13 proteins are a novel family of lipid transfer proteins important for human health [1]
Mutations in VPS13A, VPS13B, VPS13C and VPS13D are associated with the neurodegenerative disorder Chorea-Acanthocytosis (ChAc), Cohen Syndrome, Parkinson’s Disease, and a form of cerebellar ataxia, respectively [2,3,4,5,6,7]
Proper localization of the VPS13 paralogs is important in human cells, since mutations in the Vps13 adaptor binding domain (VAB) domains of VPS13A and VPS13D are associated with neurological defects and a missense mutation in the VPS13A VAB domain abolishes localization to lipid droplets [2,26,27]. These results suggest that, like yeast, human VPS13 family proteins are localized to membrane contact sites through interaction with adaptor proteins via the VAB domain to mediate lipid transfer between organelles

Summary

Introduction

The VPS13 proteins are a novel family of lipid transfer proteins important for human health [1]. Yeast VPS13 is required for a variety of different cellular processes, including (1) the proper trafficking of the vacuolar protein carboxypeptidase Y (CPY). (3) Mitochondrial homeostasis: VPS13 becomes essential for growth when lipid transfer by the ER-mitochondrion encounter site (ERMES) complex is disrupted [12,13]. Vps localizes to a number of different membrane contact sites within the yeast cell [12,13,15]. Membrane contact sites are connections between the limiting membranes of different organelles and serve as a point of transfer for lipids and metabolites between organelles [16,17]. In cells grown in glucose, Vps is predominantly on endosomes and at endosome–mitochondrion contact sites [12,13].

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