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    • Glutathione-dependent Depalmitoylation of Phospholemman by Peroxiredoxin 6

    Jacqueline Howie,Lindsay B. Tulloch,Elaine Brown,Louise Reilly,Fiona B. Ashford,Jennifer Kennedy,Krzysztof J. Wypijewski,Karen L. Aughton, Jason K. C. Mak,Michael J. Shattock,Niall J. Fraser,William Fuller

    Cell reports（2024）

    Univ Glasgow | Univ Dundee | Kings Coll London

    Cited 1|Views12
    Abstract
    Summary: Phospholemman (PLM) regulates the cardiac sodium pump: PLM phosphorylation activates the pump whereas PLM palmitoylation inhibits its activity. Here, we show that the anti-oxidant protein peroxiredoxin 6 (Prdx6) interacts with and depalmitoylates PLM in a glutathione-dependent manner. Glutathione loading cells acutely reduce PLM palmitoylation; glutathione depletion significantly increases PLM palmitoylation. Prdx6 silencing abolishes these effects, suggesting that PLM can be depalmitoylated by reduced Prdx6. In vitro, only recombinant Prdx6, among several peroxiredoxin isoforms tested, removes palmitic acid from recombinant palmitoylated PLM. The broad-spectrum depalmitoylase inhibitor palmostatin B prevents Prdx6-dependent PLM depalmitoylation in cells and in vitro. Our data suggest that Prdx6 is a thioesterase that can depalmitoylate proteins by nucleophilic attack via its reactive thiol, linking PLM palmitoylation and hence sodium pump activity to cellular glutathione status. We show that protein depalmitoylation can occur via a catalytic cysteine in which substrate specificity is determined by a protein-protein interaction.
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    Key words
    deacylation,thioesterase,sodium pump,Na/K ATPase,peroxiredoxin,FXYD,phospholemman,glutathione
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    【要点】：研究发现抗氧化蛋白Prdx6能够依赖谷胱甘肽（glutathione）去饱和化心肌钠泵调节蛋白PLM的棕榈酰化（depalmitoylation），这一发现创新性地将PLM的棕榈酰化与细胞谷胱甘肽水平联系起来，影响钠泵活动。
    

    【方法】：通过谷胱甘肽加载或耗竭细胞来操控PLM的棕榈酰化水平，并通过基因沉默技术验证Prdx6在去饱和化过程中的作用。
    

    【实验】：实验表明，Prdx6特异性地去除了体外重组的棕榈酰化PLM中的棕榈酸，并且这一过程可以被广谱的棕榈酰化抑制剂palmostatin B所阻止。此外，研究还证明了Prdx6通过其活性硫醇基团进行核苷酸攻击去饱和化PLM，揭示了蛋白质去饱和化可以通过催化半胱氨酸实现，并且底物特异性由蛋白质-蛋白质相互作用决定。使用的数据集未在摘要中提及。