title: Protective role of Gipie, a Girdin family protein, in endoplasmic reticulum stress responses in endothelial cells.
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.
authors.affiliation: Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Etsushi
authors.initials: E
authors.lastname: Matsushita
authors.forename: Naoya
authors.initials: N
authors.lastname: Asai
authors.forename: Atsushi
authors.initials: A
authors.lastname: Enomoto
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Kawamoto
authors.forename: Takuya
authors.initials: T
authors.lastname: Kato
authors.forename: Shinji
authors.initials: S
authors.lastname: Mii
authors.forename: Kengo
authors.initials: K
authors.lastname: Maeda
authors.forename: Rei
authors.initials: R
authors.lastname: Shibata
authors.forename: Shun
authors.initials: S
authors.lastname: Hattori
authors.forename: Minako
authors.initials: M
authors.lastname: Hagikura
authors.forename: Ken
authors.initials: K
authors.lastname: Takahashi
authors.forename: Masahiro
authors.initials: M
authors.lastname: Sokabe
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Murakumo
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Murohara
authors.forename: Masahide
authors.initials: M
authors.lastname: Takahashi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D019556:COS Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D004789:Enzyme Activation; D006056:Golgi Apparatus / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology; D013314:Stress, Mechanical; D020298:U937 Cells; D056811:Unfolded Protein Response / Q000502:physiology*; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C502451:CCDC88A protein, human; C559603:CCDC88B protein, human; D002352:Carrier Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D033921:Vesicular Transport Proteins; C403982:ERN2 protein, human; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D004722:Endoribonucleases