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Phospholipid flippases and Sfk1p, a novel regulator of phospholipid asymmetry, contribute to low permeability of the plasma membrane

Phospholipid flippase (type 4 P-type ATPase) plays a major role in the generation of phospholipid asymmetry in eukaryotic cell membranes. Loss of Lem3p-Dnf1/2p flippases leads to the exposure of phosphatidylserine (PS) and phosphatidylethanolamine (PE) on the cell surface in yeast, resulting in sens...

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Autores principales: Mioka, Tetsuo, Fujimura-Kamada, Konomi, Mizugaki, Nahiro, Kishimoto, Takuma, Sano, Takamitsu, Nunome, Hitoshi, Williams, David E., Andersen, Raymond J., Tanaka, Kazuma
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5935070/
https://www.ncbi.nlm.nih.gov/pubmed/29540528
http://dx.doi.org/10.1091/mbc.E17-04-0217
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author Mioka, Tetsuo
Fujimura-Kamada, Konomi
Mizugaki, Nahiro
Kishimoto, Takuma
Sano, Takamitsu
Nunome, Hitoshi
Williams, David E.
Andersen, Raymond J.
Tanaka, Kazuma
author_facet Mioka, Tetsuo
Fujimura-Kamada, Konomi
Mizugaki, Nahiro
Kishimoto, Takuma
Sano, Takamitsu
Nunome, Hitoshi
Williams, David E.
Andersen, Raymond J.
Tanaka, Kazuma
author_sort Mioka, Tetsuo
collection PubMed
description Phospholipid flippase (type 4 P-type ATPase) plays a major role in the generation of phospholipid asymmetry in eukaryotic cell membranes. Loss of Lem3p-Dnf1/2p flippases leads to the exposure of phosphatidylserine (PS) and phosphatidylethanolamine (PE) on the cell surface in yeast, resulting in sensitivity to PS- or PE-binding peptides. We isolated Sfk1p, a conserved membrane protein in the TMEM150/FRAG1/DRAM family, as a multicopy suppressor of this sensitivity. Overexpression of SFK1 decreased PS/PE exposure in lem3Δ mutant cells. Consistent with this, lem3Δ sfk1Δ double mutant cells exposed more PS/PE than the lem3Δ mutant. Sfk1p was previously implicated in the regulation of the phosphatidylinositol-4 kinase Stt4p, but the effect of Sfk1p on PS/PE exposure in lem3Δ was independent of Stt4p. Surprisingly, Sfk1p did not facilitate phospholipid flipping but instead repressed it, even under ATP-depleted conditions. We propose that Sfk1p negatively regulates transbilayer movement of phospholipids irrespective of directions. In addition, we showed that the permeability of the plasma membrane was dramatically elevated in the lem3Δ sfk1Δ double mutant in comparison with the corresponding single mutants. Interestingly, total ergosterol was decreased in the lem3Δ sfk1Δ mutant. Our results suggest that phospholipid asymmetry is required for the maintenance of low plasma membrane permeability.
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spelling pubmed-59350702018-07-30 Phospholipid flippases and Sfk1p, a novel regulator of phospholipid asymmetry, contribute to low permeability of the plasma membrane Mioka, Tetsuo Fujimura-Kamada, Konomi Mizugaki, Nahiro Kishimoto, Takuma Sano, Takamitsu Nunome, Hitoshi Williams, David E. Andersen, Raymond J. Tanaka, Kazuma Mol Biol Cell Articles Phospholipid flippase (type 4 P-type ATPase) plays a major role in the generation of phospholipid asymmetry in eukaryotic cell membranes. Loss of Lem3p-Dnf1/2p flippases leads to the exposure of phosphatidylserine (PS) and phosphatidylethanolamine (PE) on the cell surface in yeast, resulting in sensitivity to PS- or PE-binding peptides. We isolated Sfk1p, a conserved membrane protein in the TMEM150/FRAG1/DRAM family, as a multicopy suppressor of this sensitivity. Overexpression of SFK1 decreased PS/PE exposure in lem3Δ mutant cells. Consistent with this, lem3Δ sfk1Δ double mutant cells exposed more PS/PE than the lem3Δ mutant. Sfk1p was previously implicated in the regulation of the phosphatidylinositol-4 kinase Stt4p, but the effect of Sfk1p on PS/PE exposure in lem3Δ was independent of Stt4p. Surprisingly, Sfk1p did not facilitate phospholipid flipping but instead repressed it, even under ATP-depleted conditions. We propose that Sfk1p negatively regulates transbilayer movement of phospholipids irrespective of directions. In addition, we showed that the permeability of the plasma membrane was dramatically elevated in the lem3Δ sfk1Δ double mutant in comparison with the corresponding single mutants. Interestingly, total ergosterol was decreased in the lem3Δ sfk1Δ mutant. Our results suggest that phospholipid asymmetry is required for the maintenance of low plasma membrane permeability. The American Society for Cell Biology 2018-05-15 /pmc/articles/PMC5935070/ /pubmed/29540528 http://dx.doi.org/10.1091/mbc.E17-04-0217 Text en © 2018 Mioka et al. “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology. http://creativecommons.org/licenses/by-nc-sa/3.0/ This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License.
spellingShingle Articles
Mioka, Tetsuo
Fujimura-Kamada, Konomi
Mizugaki, Nahiro
Kishimoto, Takuma
Sano, Takamitsu
Nunome, Hitoshi
Williams, David E.
Andersen, Raymond J.
Tanaka, Kazuma
Phospholipid flippases and Sfk1p, a novel regulator of phospholipid asymmetry, contribute to low permeability of the plasma membrane
title Phospholipid flippases and Sfk1p, a novel regulator of phospholipid asymmetry, contribute to low permeability of the plasma membrane
title_full Phospholipid flippases and Sfk1p, a novel regulator of phospholipid asymmetry, contribute to low permeability of the plasma membrane
title_fullStr Phospholipid flippases and Sfk1p, a novel regulator of phospholipid asymmetry, contribute to low permeability of the plasma membrane
title_full_unstemmed Phospholipid flippases and Sfk1p, a novel regulator of phospholipid asymmetry, contribute to low permeability of the plasma membrane
title_short Phospholipid flippases and Sfk1p, a novel regulator of phospholipid asymmetry, contribute to low permeability of the plasma membrane
title_sort phospholipid flippases and sfk1p, a novel regulator of phospholipid asymmetry, contribute to low permeability of the plasma membrane
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5935070/
https://www.ncbi.nlm.nih.gov/pubmed/29540528
http://dx.doi.org/10.1091/mbc.E17-04-0217
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