Roles for endoplasmic reticulum-associated degradation and the novel endoplasmic reticulum stress response gene Derlin-3 in the ischemic heart.
Roles for endoplasmic reticulum-associated degradation and the novel endoplasmic reticulum stress response gene Derlin-3 in the ischemic heart.
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内质网相关降解和新型内质网应激反应基因derlin-3的作用。
DOI：
10.1161/circresaha.109.203901
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发表时间：
2010-02-05
影响因子：
20.1
通讯作者：
Glembotski CC
中科院分区：
文献类型：
--
作者：
Belmont PJ;Chen WJ;San Pedro MN;Thuerauf DJ;Gellings Lowe N;Gude N;Hilton B;Wolkowicz R;Sussman MA;Glembotski CC
应激，如缺血，损害粗内质网（ER）新生蛋白的折叠，激活未折叠蛋白反应（UPR），恢复有效的内质网蛋白折叠，从而导致对应激的保护。在某种程度上，UPR通过内质网相关降解（ERAD）增加最终错误折叠的内质网蛋白的降解，从而减轻内质网应激和细胞死亡。ERAD通过内质网应激调节剂激活转录因子6 （ATF6）而增加，ATF6可以诱导编码ERAD机制成分的基因。最近有研究表明，ATF6可保护小鼠心脏免受缺血性损伤；然而，ERAD尚未在心脏方面进行研究。最近的一项微阵列研究表明，编码ERAD机制重要组成部分的Derlin-3 （Derl3）基因在小鼠心脏中被ATF6强烈诱导。在本研究中，激活的ATF6在体外培养的心肌细胞和心脏中诱导了Derl3。模拟缺血（sI）激活内质网应激，在培养的肌细胞中诱导Derl3，在小鼠心肌梗死模型中也诱导Derl3。Derl3过表达增强ERAD并保护心肌细胞免受硅诱导的细胞死亡，而显性阴性的Derl3降低ERAD并增加硅诱导的心肌细胞死亡。这项研究描述了Derl3在心脏中的潜在保护作用，并且首次研究了在心脏环境中增强ERAD的功能后果。
Stresses, such as ischemia, impair folding of nascent proteins in the rough endoplasmic reticulum (ER), activating the unfolded protein response (UPR), which restores efficient ER protein folding, thus leading to protection from stress. In part, the UPR alleviates ER stress and cell death by increasing the degradation of terminally mis-folded ER proteins via ER-associated degradation (ERAD). ERAD is increased by the ER stress modulator, activating transcription factor 6 (ATF6), which can induce genes that encode components of the ERAD machinery. Recently, it was shown that the mouse heart is protected from ischemic damage by ATF6; however, ERAD has not been studied in the cardiac context. A recent microarray study showed that the Derlin-3 (Derl3) gene, which encodes an important component of the ERAD machinery, is robustly induced by ATF6 in the mouse heart. In the present study, activated ATF6 induced Derl3 in cultured cardiomyocytes, and in the heart, in vivo. Simulated ischemia (sI), which activates ER stress, induced Derl3 in cultured myocytes, and in an in vivo mouse model of myocardial infarction, Derl3 was also induced. Derl3 overexpression enhanced ERAD and protected cardiomyocytes from sI-induced cell death, while dominant-negative Derl3 decreased ERAD and increased sI-induced cardiomyocyte death. This study describes a potentially protective role for Derl3 in the heart, and is the first to investigate the functional consequences of enhancing ERAD in the cardiac context.