Valproic acid affects membrane trafficking and cell-wall integrity in fission yeast

Makoto Miyatake, Takayoshi Kuno, Ayako Kita, Kosaku Katsura, Kaoru Takegawa, Satoshi Uno, Toshiya Nabata, Reiko Sugiura

Research output: Contribution to journalArticle

23 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1695-1705
Number of pages11
JournalGenetics
Volume175
Issue number4
DOIs
Publication statusPublished - Apr 1 2007

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Schizosaccharomyces
Valproic Acid
Cell Wall
Membranes
Adaptor Protein Complex 1
Hypersensitivity
Calcineurin
Transcription Factor AP-1
Therapeutic Uses
Acid Phosphatase
Glycosylation
Epilepsy
Mutation

All Science Journal Classification (ASJC) codes

  • Genetics

Cite this

Miyatake, M., Kuno, T., Kita, A., Katsura, K., Takegawa, K., Uno, S., ... Sugiura, R. (2007). Valproic acid affects membrane trafficking and cell-wall integrity in fission yeast. Genetics, 175(4), 1695-1705. https://doi.org/10.1534/genetics.107.070946

Valproic acid affects membrane trafficking and cell-wall integrity in fission yeast. / Miyatake, Makoto; Kuno, Takayoshi; Kita, Ayako; Katsura, Kosaku; Takegawa, Kaoru; Uno, Satoshi; Nabata, Toshiya; Sugiura, Reiko.

In: Genetics, Vol. 175, No. 4, 01.04.2007, p. 1695-1705.

Research output: Contribution to journalArticle

Miyatake, M, Kuno, T, Kita, A, Katsura, K, Takegawa, K, Uno, S, Nabata, T & Sugiura, R 2007, 'Valproic acid affects membrane trafficking and cell-wall integrity in fission yeast', Genetics, vol. 175, no. 4, pp. 1695-1705. https://doi.org/10.1534/genetics.107.070946
Miyatake, Makoto ; Kuno, Takayoshi ; Kita, Ayako ; Katsura, Kosaku ; Takegawa, Kaoru ; Uno, Satoshi ; Nabata, Toshiya ; Sugiura, Reiko. / Valproic acid affects membrane trafficking and cell-wall integrity in fission yeast. In: Genetics. 2007 ; Vol. 175, No. 4. pp. 1695-1705.
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