Modulation of ER stress and apoptosis by endoplasmic reticulum calcium leak via translocon during unfolded protein response: involvement of GRP78
Modulation of ER stress and apoptosis by endoplasmic reticulum calcium leak via translocon during unfolded protein response: involvement of GRP78
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DOI：
10.1096/fj.12-218875
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发表时间：
2013-04-01
期刊：
影响因子：
4.8
通讯作者：
Van Coppenolle, Fabien
中科院分区：
文献类型：
--
作者：
Hammadi, Mehdi;Oulidi, Agathe;Van Coppenolle, Fabien
内质网 (ER) 参与许多细胞功能，包括蛋白质折叠和 Ca2+ 稳态。细胞对内质网应激的反应能力对于细胞的生存至关重要，这种调节的破坏可能导致细胞凋亡。内质网应激伴随着 Ca2+ 稳态的改变，内质网 Ca2+ 储备的消耗本身可以诱导内质网应激和细胞凋亡。尽管如此，响应内质网应激而激活的内质网 Ca2+ 渗漏通道的特征仍然很差。在这里，我们证明了内质网应激期间内质网 Ca2+ 的消耗是通过易位子（参与翻译的内质网蛋白复合物）发生的。许多内质网应激诱导剂会刺激内质网 Ca2+ 渗漏，而易位子抑制剂茴香霉素可以防止这种渗漏。 GRP78（一种 ER 应激标记物）的表达在用嘌呤霉素（一种易位子开启剂）处理后增加，并被茴香霉素抑制，证实了易位子在 ER 应激诱导中的主要作用。茴香霉素抑制 ER 储存消耗可显着减少 ER 应激诱导剂刺激的细胞凋亡。我们认为易位子的开放受到 GRP78 的生理调节，特别是在内质网应激期间。调节 ER Ca2+ 通透性和随后的 ER 应激的能力可以导致开发一种新的治疗方法。-Hammadi, M.、Oulidi, A.、Gackiere, F.、Katsogiannou, M.、Slomianny, C.、Roudbaraki, M.、Dewailly, E.、Delcourt, P.、Lepage, G.、Lotteau, S.、Ducreux, S.、Prevarskaya, N.，Van Coppenolle，F.未折叠蛋白反应期间内质网钙渗漏通过易位子调节 ER 应激和细胞凋亡：GRP78 的参与。 FASEB J. 27, 1600-1609 (2013)。 www.fasebj.org
The endoplasmic reticulum (ER) is involved in many cellular functions, including protein folding and Ca2+ homeostasis. The ability of cells to respond to the ER stress is critical for cell survival, and disruption in such regulation can lead to apoptosis. ER stress is accompanied by alterations in Ca2+ homeostasis, and the ER Ca2+ store depletion by itself can induce ER stress and apoptosis. Despite that, the ER Ca2+ leak channels activated in response to the ER stress remain poorly characterized. Here we demonstrate that ER Ca2+ depletion during the ER stress occurs via translocon, the ER protein complex involved in translation. Numerous ER stress inducers stimulate the ER Ca2+ leak that can be prevented by translocon inhibitor, anisomycin. Expression of GRP78, an ER stress marker, increased following treatment with puromycin (a translocon opener) and was suppressed by anisomycin, confirming a primary role of translocon in ER stress induction. Inhibition of ER store depletion by anisomycin significantly reduces apoptosis stimulated by the ER stress inducers. We suggest that translocon opening is physiologically modulated by GRP78, particularly during the ER stress. The ability to modulate the ER Ca2+ permeability and subsequent ER stress can lead to development of a novel therapeutic approach.-Hammadi, M., Oulidi, A., Gackiere, F., Katsogiannou, M., Slomianny, C., Roudbaraki, M., Dewailly, E., Delcourt, P., Lepage, G., Lotteau, S., Ducreux, S., Prevarskaya, N., Van Coppenolle, F. Modulation of ER stress and apoptosis by endoplasmic reticulum calcium leak via translocon during unfolded protein response: involvement of GRP78. FASEB J. 27, 1600-1609 (2013). www.fasebj.org