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

Cell Death Differ. 2017 Sep;24(9):1518-1529. doi: 10.1038/cdd.2017.35. Epub 2017 Jun 23.


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.

MeSH terms

  • Activating Transcription Factor 4 / metabolism
  • Animals
  • Apoptosis / drug effects
  • Cell Death / drug effects
  • Endoplasmic Reticulum Chaperone BiP
  • Endoplasmic Reticulum Stress / drug effects*
  • Fibrinolytic Agents / pharmacology
  • Heat-Shock Proteins / metabolism*
  • Mice
  • Neurons / cytology*
  • Neurons / drug effects
  • Neurons / metabolism*
  • Protein Serine-Threonine Kinases / metabolism
  • Signal Transduction / drug effects
  • Thromboembolism / therapy
  • Tissue Plasminogen Activator / pharmacology
  • Unfolded Protein Response / drug effects


  • Atf4 protein, mouse
  • Endoplasmic Reticulum Chaperone BiP
  • Fibrinolytic Agents
  • Heat-Shock Proteins
  • Hspa5 protein, mouse
  • Activating Transcription Factor 4
  • Protein Serine-Threonine Kinases
  • eIF2alpha kinase, mouse
  • Tissue Plasminogen Activator