Protective role of Gipie, a Girdin family protein, in endoplasmic reticulum stress responses in endothelial cells.
Protective role of Gipie, a Girdin family protein, in endoplasmic reticulum stress responses in endothelial cells.
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DOI：
10.1091/mbc.e10-08-0724
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发表时间：
2011-03-15
影响因子：
3.3
通讯作者：
Takahashi M
中科院分区：
文献类型：
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作者：
Matsushita E;Asai N;Enomoto A;Kawamoto Y;Kato T;Mii S;Maeda K;Shibata R;Hattori S;Hagikura M;Takahashi K;Sokabe M;Murakumo Y;Murohara T;Takahashi M
Gipie/GRP78 相互作用充当调节细胞凋亡信号通路的分子开关，这似乎有助于保护内皮细胞免受内质网应激诱导的细胞凋亡。内皮细胞持续暴露于机械/剪切应力下会引发未折叠蛋白反应（UPR），从而增强细胞内稳态并保护细胞免受不正确折叠蛋白的积累。当细胞受到持续的高内质网（ER）应激时，除非维持稳态，否则细胞会发生凋亡。目前尚不清楚内皮细胞如何差异调节 UPR。在这里，我们展示了一种新型 Girdin 家族蛋白 Gipie（内质网应激诱导的 78 kDa 葡萄糖调节蛋白 [GRP78] 相互作用蛋白）在内皮细胞中表达，并与 UPR 的主要调节因子 GRP78 相互作用。 Gipie 稳定了 ER 上 GRP78 和 ER 应激传感器肌醇需求蛋白 1 (IRE1) 之间的相互作用，导致 IRE1 诱导的 c-Jun N 末端激酶 (JNK) 激活减弱。 Gipie 表达在 ER 应激时被诱导，并抑制 IRE1-JNK 通路和 ER 应激诱导的细胞凋亡。此外，我们发现在大鼠模型中球囊损伤后，颈动脉新内膜中的 Gipie 表达上调，已知这会导致 UPR 的诱导。因此，我们的数据表明 Gipie/GRP78 相互作用控制 IRE1-JNK 信号通路。在动脉粥样硬化和血管内皮功能障碍等病理情况下，这种相互作用似乎可以保护内皮细胞免受内质网应激诱导的细胞凋亡。
The Gipie/GRP78 interaction serves as a molecular switch for the regulation of the apoptotic signaling pathway, which appears to contribute to the protection of endothelial cells from endoplasmic reticulum stress-induced apoptosis. Continued exposure of endothelial cells to mechanical/shear stress elicits the unfolded protein response (UPR), which enhances intracellular homeostasis and protect cells against the accumulation of improperly folded proteins. Cells commit to apoptosis when subjected to continuous and high endoplasmic reticulum (ER) stress unless homeostasis is maintained. It is unknown how endothelial cells differentially regulate the UPR. Here we show that a novel Girdin family protein, Gipie (78 kDa glucose-regulated protein [GRP78]-interacting protein induced by ER stress), is expressed in endothelial cells, where it interacts with GRP78, a master regulator of the UPR. Gipie stabilizes the interaction between GRP78 and the ER stress sensor inositol-requiring protein 1 (IRE1) at the ER, leading to the attenuation of IRE1-induced c-Jun N-terminal kinase (JNK) activation. Gipie expression is induced upon ER stress and suppresses the IRE1-JNK pathway and ER stress-induced apoptosis. Furthermore we found that Gipie expression is up-regulated in the neointima of carotid arteries after balloon injury in a rat model that is known to result in the induction of the UPR. Thus our data indicate that Gipie/GRP78 interaction controls the IRE1-JNK signaling pathway. That interaction appears to protect endothelial cells against ER stress-induced apoptosis in pathological contexts such as atherosclerosis and vascular endothelial dysfunction.