RRC ID 2226
Author Miyatake M, Kuno T, Kita A, Katsura K, Takegawa K, Uno S, Nabata T, Sugiura R.
Title Valproic acid affects membrane trafficking and cell-wall integrity in fission yeast.
Journal Genetics
Abstract Valproic acid (VPA) is widely used to treat epilepsy and manic-depressive illness. Although VPA has been reported to exert a variety of biochemical effects, the exact mechanisms underlying its therapeutic effects remain elusive. To gain further insights into the molecular mechanisms of VPA action, a genetic screen for fission yeast mutants that show hypersensitivity to VPA was performed. One of the genes that we identified was vps45+, which encodes a member of the Sec1/Munc18 family that is implicated in membrane trafficking. Notably, several mutations affecting membrane trafficking also resulted in hypersensitivity to VPA. These include ypt3+ and ryh1+, both encoding a Rab family protein, and apm1+, encoding the mu1 subunit of the adaptor protein complex AP-1. More importantly, VPA caused vacuolar fragmentation and inhibited the glycosylation and the secretion of acid phosphatase in wild-type cells, suggesting that VPA affects membrane trafficking. Interestingly, the cell-wall-damaging agents such as micafungin or the inhibition of calcineurin dramatically enhanced the sensitivity of wild-type cells to VPA. Consistently, VPA treatment of wild-type cells enhanced their sensitivity to the cell-wall-digesting enzymes. Altogether, our results suggest that VPA affects membrane trafficking, which leads to the enhanced sensitivity to cell-wall damage in fission yeast.
Volume 175(4)
Pages 1695-705
Published 2007-4-1
DOI 10.1534/genetics.107.070946
PII genetics.107.070946
PMID 17287531
PMC PMC1855103
MeSH Amino Acid Sequence Base Sequence Biological Transport, Active / drug effects Calcineurin / metabolism Cell Membrane / drug effects Cell Membrane / metabolism Cell Wall / drug effects Cell Wall / ultrastructure DNA, Fungal / genetics Drug Resistance, Fungal / genetics Genes, Fungal Microscopy, Electron Mutation Schizosaccharomyces / drug effects* Schizosaccharomyces / genetics Schizosaccharomyces / metabolism* Schizosaccharomyces / ultrastructure Schizosaccharomyces pombe Proteins / genetics Schizosaccharomyces pombe Proteins / metabolism Sequence Homology, Amino Acid Signal Transduction / drug effects Valproic Acid / pharmacology* Vesicular Transport Proteins / genetics Vesicular Transport Proteins / metabolism
IF 4.015
Times Cited 23
Yeast HM123