Activation of cell surface GRP78 decreases endoplasmic reticulum stress and neuronal death

This project was supported by the Region Basse-Normandie and the AXA postdoctoral fellowship program, the INSERM, and the university of Caen. We thank Mr Gilbert Pigree and Mr Maxime Lemarchand for their help with the production of radioactive tPA (IMOGERE platform, University of Caen, France). Thanks to Dr Mario Gonzalez-Gronow for the gift of recombinant Grp78International audienceThe 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-eIF2α 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