Department of Physiology and Groupe de Recherche Axé sur la Structure des Protéines, McGill University, Montréal, QC H3E 1Y6, Canada.
Mol Biol Cell. 2013 Dec;24(24):3787-804. doi: 10.1091/mbc.E13-07-0417. Epub 2013 Oct 23.
Membrane trafficking in concert with the peripheral quality control machinery plays a critical role in preserving plasma membrane (PM) protein homeostasis. Unfortunately, the peripheral quality control may also dispose of partially or transiently unfolded polypeptides and thereby contribute to the loss-of-expression phenotype of conformational diseases. Defective functional PM expression of the human ether-a-go-go-related gene (hERG) K(+) channel leads to the prolongation of the ventricular action potential that causes long QT syndrome 2 (LQT2), with increased propensity for arrhythmia and sudden cardiac arrest. LQT2 syndrome is attributed to channel biosynthetic processing defects due to mutation, drug-induced misfolding, or direct channel blockade. Here we provide evidence that a peripheral quality control mechanism can contribute to development of the LQT2 syndrome. We show that PM hERG structural and metabolic stability is compromised by the reduction of extracellular or intracellular K(+) concentration. Cardiac glycoside-induced intracellular K(+) depletion conformationally impairs the complex-glycosylated channel, which provokes chaperone- and C-terminal Hsp70-interacting protein-dependent polyubiquitination, accelerated internalization, and endosomal sorting complex required for transport-dependent lysosomal degradation. A similar mechanism contributes to the down-regulation of PM hERG harboring LQT2 missense mutations, with incomplete secretion defect. These results suggest that PM quality control plays a determining role in the loss-of-expression phenotype of hERG in certain hereditary and acquired LTQ2 syndromes.
膜运输与外周质量控制系统协同作用，对于维持质膜（PM）蛋白的内稳态起着至关重要的作用。不幸的是，外周质量控制系统也可能会处理部分或瞬时展开的多肽，从而导致构象疾病的表达缺失表型。人醚-去甲肾上腺素相关基因（hERG）K(+)通道的功能性 PM 表达缺陷导致心室动作电位延长，引起长 QT 综合征 2（LQT2），心律失常和心搏骤停的风险增加。LQT2 综合征归因于通道生物合成加工缺陷，原因是突变、药物诱导的错误折叠或直接通道阻断。在这里，我们提供证据表明，外周质量控制机制可能导致 LQT2 综合征的发展。我们表明，PM hERG 的结构和代谢稳定性受到细胞外或细胞内 K(+)浓度降低的影响。心脏糖苷诱导的细胞内 K(+)耗竭会使复杂糖基化的通道构象受损，从而引发伴侣蛋白和 C 端 Hsp70 相互作用蛋白依赖性多泛素化、加速内化和内体分选复合物所需的运输依赖性溶酶体降解。类似的机制导致携带 LQT2 错义突变的 PM hERG 的下调，伴有不完全的分泌缺陷。这些结果表明，PM 质量控制在某些遗传性和获得性 LTQ2 综合征中 hERG 的表达缺失表型中起着决定性作用。
