Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD, 21205, USA.
Division of Cardiology, McAllister Heart Institute, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
Nat Commun. 2020 Oct 20;11(1):5237. doi: 10.1038/s41467-020-18980-x.
Proteotoxicity from insufficient clearance of misfolded/damaged proteins underlies many diseases. Carboxyl terminus of Hsc70-interacting protein (CHIP) is an important regulator of proteostasis in many cells, having E3-ligase and chaperone functions and often directing damaged proteins towards proteasome recycling. While enhancing CHIP functionality has broad therapeutic potential, prior efforts have all relied on genetic upregulation. Here we report that CHIP-mediated protein turnover is markedly post-translationally enhanced by direct protein kinase G (PKG) phosphorylation at S20 (mouse, S19 human). This increases CHIP binding affinity to Hsc70, CHIP protein half-life, and consequent clearance of stress-induced ubiquitinated-insoluble proteins. PKG-mediated CHIP-pS20 or expressing CHIP-S20E (phosphomimetic) reduces ischemic proteo- and cytotoxicity, whereas a phospho-silenced CHIP-S20A amplifies both. In vivo, depressing PKG activity lowers CHIP-S20 phosphorylation and protein, exacerbating proteotoxicity and heart dysfunction after ischemic injury. CHIP-S20E knock-in mice better clear ubiquitinated proteins and are cardio-protected. PKG activation provides post-translational enhancement of protein quality control via CHIP.
蛋白毒性是由于错误折叠/受损蛋白质的清除不足引起的，它是许多疾病的基础。热休克蛋白 70 相互作用蛋白（CHIP）羧基末端是许多细胞中蛋白质稳态的重要调节剂，具有 E3 连接酶和伴侣功能，通常将受损蛋白质导向蛋白酶体回收。虽然增强 CHIP 的功能具有广泛的治疗潜力，但之前的所有努力都依赖于遗传上调。在这里，我们报告 CHIP 介导的蛋白质周转通过直接蛋白激酶 G（PKG）在 S20 处（小鼠，S19 人）的磷酸化显著地进行翻译后增强。这增加了 CHIP 与 Hsc70 的结合亲和力、CHIP 蛋白半衰期，以及随后应激诱导的泛素化不溶性蛋白的清除。PKG 介导的 CHIP-pS20 或表达 CHIP-S20E（磷酸模拟物）减少缺血性蛋白毒性和细胞毒性，而磷酸沉默的 CHIP-S20A 则放大了两者。在体内，降低 PKG 活性会降低 CHIP-S20 磷酸化和蛋白水平，从而加剧缺血性损伤后的蛋白毒性和心脏功能障碍。CHIP-S20E 敲入小鼠更好地清除泛素化蛋白并具有心脏保护作用。PKG 激活通过 CHIP 提供蛋白质质量控制的翻译后增强。
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