Scholarlink

<p>The aminoglycoside antibiotic neomycin has robust antibacterial properties, yet its clinical utility is curtailed by its nephrotoxicity and ototoxicity. The mechanism by which the polycationic neomycin enters specific eukaryotic cell types remains poorly understood. In budding yeast, <i>NEO1</i> is required for neomycin resistance and encodes a phospholipid flippase that establishes membrane asymmetry. Here we show that mutations altering Neo1 substrate recognition cause neomycin hypersensitivity by exposing phosphatidylinositol-4-phosphate (PI4P) in the plasma membrane extracellular leaflet. Cryogenic electron microscopy reveals PI4P binding to Neo1 within the substrate translocation pathway. PI4P enters the lumen of the endoplasmic reticulum and is flipped by Neo1 at the Golgi to prevent PI4P secretion to the cell surface. Deficiency of the orthologous ATP9A in human cells also causes exposure of PI4P and neomycin sensitivity. These findings unveil conserved mechanisms of aminoglycoside sensitivity and phosphoinositide homoeostasis, with important implications for signalling by extracellular phosphoinositides.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

P4-ATPases control phosphoinositide membrane asymmetry and neomycin resistance

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年7月11日

查看全文
  • Bhawik K. Jain,
  • H. Diessel Duan,
  • Christina Valentine,
  • Ariana Samiha,
  • Huilin Li,
  • Todd R. Graham

摘要

The aminoglycoside antibiotic neomycin has robust antibacterial properties, yet its clinical utility is curtailed by its nephrotoxicity and ototoxicity. The mechanism by which the polycationic neomycin enters specific eukaryotic cell types remains poorly understood. In budding yeast, NEO1 is required for neomycin resistance and encodes a phospholipid flippase that establishes membrane asymmetry. Here we show that mutations altering Neo1 substrate recognition cause neomycin hypersensitivity by exposing phosphatidylinositol-4-phosphate (PI4P) in the plasma membrane extracellular leaflet. Cryogenic electron microscopy reveals PI4P binding to Neo1 within the substrate translocation pathway. PI4P enters the lumen of the endoplasmic reticulum and is flipped by Neo1 at the Golgi to prevent PI4P secretion to the cell surface. Deficiency of the orthologous ATP9A in human cells also causes exposure of PI4P and neomycin sensitivity. These findings unveil conserved mechanisms of aminoglycoside sensitivity and phosphoinositide homoeostasis, with important implications for signalling by extracellular phosphoinositides.