Ubiquitination-dependent quality control of hERG K+ channel with acquired and inherited conformational defect at the plasma membrane.
Ubiquitination-dependent quality control of hERG K+ channel with acquired and inherited conformational defect at the plasma membrane.
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DOI：
10.1091/mbc.e13-07-0417
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发表时间：
2013-12
影响因子：
3.3
通讯作者：
Shrier A
中科院分区：
文献类型：
--
作者：
Apaja PM;Foo B;Okiyoneda T;Valinsky WC;Barriere H;Atanasiu R;Ficker E;Lukacs GL;Shrier A
质膜质量控制机制在长QT综合征表型的发展中的作用被证明，该表型是由包括心肌细胞在内的多种表达系统中Herg钾通道的获得性和遗传性构象缺陷引起的。膜转运与外周质量控制机制在维持质膜(PM)蛋白质动态平衡方面起着关键作用。不幸的是，外周质量控制也可能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。人类乙醚-a-GO-GO相关基因(HERG)K+通道的功能性PM表达缺陷会导致心室动作电位延长，从而导致长QT综合征2(LQT2)，增加心律失常和心脏骤停的倾向。LQT2综合征是由于突变、药物诱导的错误折叠或直接的通道阻断而导致的通道生物合成加工缺陷。在这里，我们提供的证据表明，外周质量控制机制可能有助于LQT2综合征的发展。我们发现，PM HERG的结构和代谢稳定性因细胞外或细胞内K+浓度的降低而受到损害。心脏糖苷诱导的细胞内K+耗竭损伤了复合体糖基化通道，从而引起伴侣和C末端相互作用的蛋白依赖的多泛素化，加速内化，以及运输依赖的溶酶体降解所需的内体分选复合体。类似的机制有助于PM Herg下调含有LQT2错义突变的PM Herg，具有不完全分泌缺陷。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决定性作用。
The role of the plasma membrane quality control machinery is demonstrated in the development of the long QT syndrome phenotype, caused by acquired and inherited conformational defects of the hERG potassium channel in multiple expression systems, including cardiac myocytes. 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.