Genome-wide analysis reveals the vacuolar pH-stat of Saccharomyces cerevisiae

Autor: Laura Kallay, Richard Green, Zhaolin Hua, Todd R. Graham, Christopher L. Brett, Yongqiang Zhang, Mark Donowitz, Rajini Rao, Anthony Chyou
Jazyk: angličtina
Rok vydání: 2011
Předmět:
Genetic Screens
ATPase
Mutant
lcsh:Medicine
Yeast and Fungal Models
Vacuole
0302 clinical medicine
Molecular Cell Biology
Homeostasis
lcsh:Science
Phospholipids
Cellular Stress Responses
0303 health sciences
Multidisciplinary
ATP synthase
Systems Biology
Niemann-Pick Disease
Type C
Genomics
Hydrogen-Ion Concentration
Cellular Structures
Cell biology
Functional Genomics
Sterols
Biochemistry
Membranes and Sorting
Genome
Fungal
Research Article
Receptor recycling
Vacuolar Proton-Translocating ATPases
Saccharomyces cerevisiae
Biology
03 medical and health sciences
Model Organisms
Genetics
Humans
Genetic Testing
Transport Vesicles
030304 developmental biology
lcsh:R
Biological Transport
biology.organism_classification
Subcellular Organelles
Membrane biogenesis
Mutation
Vacuoles
biology.protein
lcsh:Q
Lysosomes
030217 neurology & neurosurgery
Zdroj: PLoS ONE, Vol 6, Iss 3, p e17619 (2011)
PLoS ONE
ISSN: 1932-6203
Popis: Protons, the smallest and most ubiquitous of ions, are central to physiological processes. Transmembrane proton gradients drive ATP synthesis, metabolite transport, receptor recycling and vesicle trafficking, while compartmental pH controls enzyme function. Despite this fundamental importance, the mechanisms underlying pH homeostasis are not entirely accounted for in any organelle or organism. We undertook a genome-wide survey of vacuole pH (pH(v)) in 4,606 single-gene deletion mutants of Saccharomyces cerevisiae under control, acid and alkali stress conditions to reveal the vacuolar pH-stat. Median pH(v) (5.27±0.13) was resistant to acid stress (5.28±0.14) but shifted significantly in response to alkali stress (5.83±0.13). Of 107 mutants that displayed aberrant pH(v) under more than one external pH condition, functional categories of transporters, membrane biogenesis and trafficking machinery were significantly enriched. Phospholipid flippases, encoded by the family of P4-type ATPases, emerged as pH regulators, as did the yeast ortholog of Niemann Pick Type C protein, implicated in sterol trafficking. An independent genetic screen revealed that correction of pH(v) dysregulation in a neo1(ts) mutant restored viability whereas cholesterol accumulation in human NPC1(-/-) fibroblasts diminished upon treatment with a proton ionophore. Furthermore, while it is established that lumenal pH affects trafficking, this study revealed a reciprocal link with many mutants defective in anterograde pathways being hyperacidic and retrograde pathway mutants with alkaline vacuoles. In these and other examples, pH perturbations emerge as a hitherto unrecognized phenotype that may contribute to the cellular basis of disease and offer potential therapeutic intervention through pH modulation.
Databáze: OpenAIRE
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