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Valproic Acid Affects Membrane Trafficking and Cell-Wall Integrity in Fission Yeast

Authors
  • Makoto Miyatake
  • Takayoshi Kuno
  • Ayako Kita
  • Kosaku Katsura
  • Kaoru Takegawa
  • Satoshi Uno
  • Toshiya Nabata
  • Reiko Sugiura
Publisher
Copyright © 2007 by the Genetics Society of America
Publication Date
Apr 01, 2007
Source
PMC
Keywords
Disciplines
  • Biology
  • Chemistry
  • Medicine
License
Unknown

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 μ1 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.

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