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

作者：Louessard Morgane; Bardou Isabelle; Lemarchand Eloise; Thiebaut Audrey M; Parcq Jerome; Leprince Jerome; Terrisse Anne; Carraro Valerie; Fafournoux Pierre; Bruhat Alain; Orset Cyrille; Vivien Denis; Ali Carine; Roussel Benoit D^*

来源：Cell Death and Differentiation, 2017, 24(9): 1518-1529.

DOI：10.1038/cdd.2017.35

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.

• 出版日期2017-9