Serine/threonine protein phosphatase 5 (PP5) is ubiquitously expressed in eukaryotic cells; however, its function in cardiomyocytes is unknown. Under basal conditions, PP5 is autoinhibited, but enzymatic activity rises upon binding of specific factors, such as the chaperone Hsp90. Here we show that PP5 binds and dephosphorylates the elastic N2B-unique sequence (N2Bus) of titin in cardiomyocytes. Using various binding and phosphorylation tests, cell-culture manipulation, and transgenic mouse hearts, we demonstrate that PP5 associates with N2Bus in vitro and in sarcomeres and is antagonistic to several protein kinases, which phosphorylate N2Bus and lower titin-based passive tension. PP5 is pathologically elevated and likely contributes to hypo-phosphorylation of N2Bus in failing human hearts. Furthermore, Hsp90-activated PP5 interacts with components of a sarcomeric, N2Bus-associated, mechanosensor complex, and blocks mitogen-activated protein-kinase signaling in this complex. Our work establishes PP5 as a compartmentalized, well-controlled phosphatase in cardiomyocytes, which regulates titin properties and kinase signaling at the myofilaments.

中文翻译：

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蛋白磷酸酶5调节心肌细胞中肌节相关的机械传感器复合物的肌动蛋白磷酸化和功能。

丝氨酸/苏氨酸蛋白磷酸酶5（PP5）在真核细胞中普遍表达；然而，其在心肌细胞中的功能尚不清楚。在基础条件下，PP5是自抑制的，但是在结合诸如伴侣蛋白Hsp90的特定因子时，酶活性会升高。在这里，我们显示PP5结合并磷酸化心肌细胞中titin的弹性N2B唯一序列（N2Bus）。使用各种结合和磷酸化测试，细胞培养操作和转基因小鼠心脏，我们证明PP5在体外和肉瘤中与N2Bus缔合，并且对几种蛋白激酶具有拮抗作用，后者使N2Bus磷酸化并降低基于titin的被动张力。PP5在病理上升高，并且可能导致衰竭的人类心脏中N2Bus的磷酸化过低。此外，Hsp90激活的PP5与与N2Bus相关的肌节机械传感器复合物的成分相互作用，并在该复合物中阻断促分裂原激活的蛋白激酶信号转导。我们的工作将PP5建立为心肌细胞中的一个分区化的，受控良好的磷酸酶，它调节肌丝上的titin特性和激酶信号传导。