title: Valproic acid affects membrane trafficking and cell-wall integrity in fission yeast.
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.
authors.affiliation: Division of Molecular Pharmacology and Pharmacogenomics, Department of Genome Sciences, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Miyatake
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Kuno
authors.forename: Ayako
authors.initials: A
authors.lastname: Kita
authors.forename: Kosaku
authors.initials: K
authors.lastname: Katsura
authors.forename: Kaoru
authors.initials: K
authors.lastname: Takegawa
authors.forename: Satoshi
authors.initials: S
authors.lastname: Uno
authors.forename: Toshiya
authors.initials: T
authors.lastname: Nabata
authors.forename: Reiko
authors.initials: R
authors.lastname: Sugiura
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D001693:Biological Transport, Active / Q000187:drug effects; D019703:Calcineurin / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002473:Cell Wall / Q000187:drug effects / Q000648:ultrastructure; D004271:DNA, Fungal / Q000235:genetics; D025141:Drug Resistance, Fungal / Q000235:genetics; D005800:Genes, Fungal; D008854:Microscopy, Electron; D009154:Mutation; D012568:Schizosaccharomyces / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D029702:Schizosaccharomyces pombe Proteins / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000187:drug effects; D014635:Valproic Acid / Q000494:pharmacology*; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D004271:DNA, Fungal; D029702:Schizosaccharomyces pombe Proteins; D033921:Vesicular Transport Proteins; D014635:Valproic Acid; D019703:Calcineurin