Protective role of Gipie, a Girdin family protein, in endoplasmic reticulum stress responses in endothelial cells

Etsushi Matsushita, Naoya Asai, Atsushi Enomoto, Yoshiyuki Kawamoto, Takuya Kato, Shinji Mii, Kengo Maeda, Rei Shibata, Shun Hattori, Minako Hagikura, Ken Takahashi, Masahiro Sokabe, Yoshiki Murakumo, Toyoaki Murohara, Masahide Takahashi

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Continued exposure of endothelial cells to mechanical/shear stress elicits the unfolded protein response (UPR), which enhances intracellular homeostasis and protect cells against the accumulation of improperly folded proteins. Cells commit to apoptosis when subjected to continuous and high endoplasmic reticulum (ER) stress unless homeostasis is maintained. It is unknown how endothelial cells differentially regulate the UPR. Here we show that a novel Girdin family protein, Gipie (78 kDa glucose-regulated protein [GRP78]-interacting protein induced by ER stress), is expressed in endothelial cells, where it interacts with GRP78, a master regulator of the UPR. Gipie stabilizes the interaction between GRP78 and the ER stress sensor inositol-requiring protein 1 (IRE1) at the ER, leading to the attenuation of IRE1-induced c-Jun N-terminal kinase (JNK) activation. Gipie expression is induced upon ER stress and suppresses the IRE1-JNK pathway and ER stress-induced apoptosis. Furthermore we found that Gipie expression is up-regulated in the neointima of carotid arteries after balloon injury in a rat model that is known to result in the induction of the UPR. Thus our data indicate that Gipie/GRP78 interaction controls the IRE1-JNK signaling pathway. That interaction appears to protect endothelial cells against ER stress-induced apoptosis in pathological contexts such as atherosclerosis and vascular endothelial dysfunction.

Original languageEnglish
Pages (from-to)736-747
Number of pages12
JournalMolecular Biology of the Cell
Volume22
Issue number6
DOIs
Publication statusPublished - Mar 15 2011
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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  • Cite this

    Matsushita, E., Asai, N., Enomoto, A., Kawamoto, Y., Kato, T., Mii, S., Maeda, K., Shibata, R., Hattori, S., Hagikura, M., Takahashi, K., Sokabe, M., Murakumo, Y., Murohara, T., & Takahashi, M. (2011). Protective role of Gipie, a Girdin family protein, in endoplasmic reticulum stress responses in endothelial cells. Molecular Biology of the Cell, 22(6), 736-747. https://doi.org/10.1091/mbc.E10-08-0724