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

Morgane Louessard 1 Isabelle Bardou 1 Eloïse Lemarchand 1 Audrey Thiebaut 1 Jérôme Parcq 1 Jérôme Leprince 2, 3 Anne Terrisse 4 Valérie Carraro 4 Pierre Fafournoux 4 Alain Bruhat 4 Cyrille Orset 1 Denis Vivien 1, 5 Carine Ali 1 Benoit Roussel 1, *
* Corresponding author
1 Sérine protéases et physiopathologie de l'unité neurovasculaire
2 DC2N - Différenciation et communication neuronale et neuroendocrine
3 PRIMACEN - Plate-Forme de Recherche en Imagerie Cellulaire de Haute-Normandie
4 UNH - Unité de Nutrition Humaine
5 UBRC - Unité de Biostatistique et de Recherche Clinique
Abstract : 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-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.
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Submitted on : Wednesday, September 13, 2017 - 11:32:47 AM
Last modification on : Thursday, November 25, 2021 - 5:00:02 PM
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Morgane Louessard, Isabelle Bardou, Eloïse Lemarchand, Audrey Thiebaut, Jérôme Parcq, et al.. Activation of cell surface GRP78 decreases endoplasmic reticulum stress and neuronal death. Cell Death and Differentiation, Nature Publishing Group, 2017, 24 (9), pp.1518-1529. ⟨10.1038/cdd.2017.35⟩. ⟨inserm-01586769⟩

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