Activation of cell surface GRP78 decreases endoplasmic reticulum stress and neuronal death
Activation of cell surface GRP78 decreases endoplasmic reticulum stress and neuronal death
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DOI：
10.1038/cdd.2017.35
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发表时间：
2017-09-01
影响因子：
12.4
通讯作者：
Roussel, Benoit D.
中科院分区：
文献类型：
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作者：
Louessard, Morgane;Bardou, Isabelle;Roussel, Benoit D.
未折叠蛋白反应（UPR）是一种与内质网（ER）相关的应激保护途径，旨在保护细胞免受应激负荷的影响。然而，当延长时，UPR激活转化为死亡信号，这依赖于其PERK-eIF2 α分支。普遍定期循环的过度激活与许多神经系统疾病有关，包括脑缺血。在此，我们利用转基因内质网应激报告小鼠的体内血栓栓塞模型和体外缺血神经元模型，证明了缺血应激导致UPR PERK分支的有害激活。此外，我们发现丝氨酸蛋白酶组织型纤溶酶原激活物（tPA）可以与细胞表面Grp78 （78 kD葡萄糖调节蛋白）结合，导致PERK通路激活减少，从而减少有害因子CHOP，最终促进神经保护。总之，这项工作强调了伴侣蛋白Grp78作为tPA的膜受体的新作用和治疗潜力，能够防止内质网应激过度激活。
The unfolded protein response (UPR) is an endoplasmic reticulum (ER) -related stress conserved pathway that aims to protect cells from being overwhelmed. However, when prolonged, UPR activation converts to a death signal, which relies on its PERK-eIF2 alpha branch. Overactivation of the UPR has been implicated in many neurological diseases, including cerebral ischaemia. Here, by using an in vivo thromboembolic model of stroke on transgenic ER stress-reporter mice and neuronal in vitro models of ischaemia, we demonstrate that ischaemic stress leads to the deleterious activation of the PERK branch of the UPR. Moreover, we show that the serine protease tissue-type plasminogen activator (tPA) can bind to cell surface Grp78 (78 kD glucose-regulated protein), leading to a decrease of the PERK pathway activation, thus a decrease of the deleterious factor CHOP, and finally promotes neuroprotection. Altogether, this work highlights a new role and a therapeutic potential of the chaperone protein Grp78 as a membrane receptor of tPA capable to prevent from ER stress overactivation.