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首页> 外文期刊>Molecular and Cellular Biology >Dilated Cardiomyopathy Caused by Aberrant Endoplasmic Reticulum Quality Control in Mutant KDEL Receptor Transgenic Mice
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Dilated Cardiomyopathy Caused by Aberrant Endoplasmic Reticulum Quality Control in Mutant KDEL Receptor Transgenic Mice

机译：突变的KDEL受体转基因小鼠内质网异常质量控制引起的扩张型心肌病

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摘要

Aberrant protein folding beyond the capacity of endoplasmic reticulum (ER) quality control leads to stress response in the ER. The Lys-Asp-Glu-Leu (KDEL) receptor, a retrieval receptor for ER chaperones in the early secretory pathway, contributes to ER quality control. To elucidate the function of the KDEL receptor in vivo, we established transgenic mice expressing a mutant KDEL receptor. We found that the mutant KDEL receptor sensitized cells to ER stress and that the mutant mice developed dilated cardiomyopathy. Ultrastructural analyses revealed expanded sarcoplasmic reticulums and protein aggregates that obstructed the adjacent transverse tubules of the mutant cardiomyocytes. Cardiomyocytes from the mutant mice were sensitive to ER stress when treated with tunicamycin and showed a functional defect in the L-type Ca2+ current. We observed ubiquitinated protein aggregates, enhanced expression of CHOP (a death-related transcriptional factor expressed upon ER stress), and apoptosis in the mutant hearts. These findings suggest that impairment of the KDEL receptor disturbs ER quality control, resulting in accumulation of misfolded proteins in the ER in an in vivo system, and that the dilated cardiomyopathy found in the mutant KDEL receptor transgenic mice is associated with ER stress.
机译：异常蛋白折叠超出内质网（ER）质量控制的能力会导致ER中的应激反应。 Lys-Asp-Glu-Leu（KDEL）受体是早期分泌途径中ER伴侣的恢复受体，有助于ER质量控制。为了阐明KDEL受体在体内的功能，我们建立了表达突变KDEL受体的转基因小鼠。我们发现突变的KDEL受体使细胞对内质网应激敏感，并且突变的小鼠发展为扩张型心肌病。超微结构分析显示，扩展的肌浆网和蛋白质聚集体阻碍了突变型心肌细胞的相邻横向小管。用衣霉素处理后，突变小鼠的心肌细胞对内质网应激敏感，并在L型Ca 2 + 电流中表现出功能缺陷。我们观察到泛素化的蛋白质聚集体，CHOP（ER应激时表达的与死亡相关的转录因子）表达增强和突变型心脏发生凋亡。这些发现表明，KDEL受体的损伤干扰了ER质量控制，导致体内系统中ER中错误折叠的蛋白积累，并且在突变的KDEL受体转基因小鼠中发现的扩张型心肌病与ER应激有关。

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