Characterization of a valproic acid-sensitive mutant allele of the Golgi GDP-mannose transmembrane transporter Vrg4 in Schizosaccharomyces pombe

TL;DR

This study identifies a mutant yeast strain sensitive to valproic acid, revealing a link between a glycosylation transporter and drug sensitivity.

Contribution

A new valproic acid-sensitive mutant allele of the GDP-mannose transporter Vrg4 is identified and characterized in fission yeast.

Findings

A missense mutation (T256I) in Vrg4 causes valproic acid sensitivity and impaired glycosylation.

Overexpression of Vrg4 negatively affects cell growth in fission yeast.

Impaired glycosylation is suggested as a potential mechanism for valproic acid sensitivity.

Abstract

Valproic acid (VPA) is a widely used drug for epilepsy. However, precise molecular mechanisms relevant to VPA's side effects remain elusive. This study identifies a VPA-sensitive mutant strain (
vas21
) in fission yeast with a missense mutation (T256I) in the nucleotide sugar-binding motif of the GDP-mannose transporter
Vrg4
. This mutation impairs protein glycosylation, as evidenced by altered acid phosphatase mobility. We also found that
Vrg4
overexpression deteriorates cell growth. Our results highlight the role of
Vrg4
in glycosylation and implicate impaired glycosylation as a potential mechanism underlying VPA sensitivity. The new allele of

vrg4

will be useful in glycobiology and pharmacology.

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