T cell receptor-mediated signaling induces GRP78 expression in T cells: the implications in maintaining T cell viability.
The 78-kDa glucose-regulated protein (GRP78) is an important molecular chaperone in the endoplasmic reticulum (ER) induced by various stresses. This study showed that stimulation with anti-CD3 mAb, PMA plus ionomycin, or an antigen increased the levels of GRP78 mRNA in primary T cells, which was inhibited by Ca(2+) chelators EGTA and BAPTA-AM and by an inhibitor of calcineurin FK506. In addition, the specific knockdown of GRP78 protein expression induced apoptosis in mouse EL-4 T cell line associated with CHOP induction and caspase-3 activation. Furthermore, overexpression of GRP78 inhibited PMA/ionomycin-induced cell death in EL-4 cells. Collectively, GRP78 expression is induced by TCR activation via a Ca(2+)-dependent pathway and may play a critical role in maintaining T cell viability in the steady and TCR-activated states. These results suggest a novel regulatory mechanism and an essential function of GRP78 in T cells.
Takano
Shinichi
S
Department of Immunology, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3898, Japan.
Ando
Takashi
T
Hiramatsu
Nobuhiko
N
Kanayama
Asuka
A
Maekawa
Shinya
S
Ohnuma
Yuko
Y
Enomoto
Nobuyuki
N
Ogawa
Hideoki
H
Paton
Adrienne W
AW
Paton
James C
JC
Kitamura
Masanori
M
Nakao
Atsuhito
A
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis; D017252:CD3 Complex / Q000276:immunology; D002470:Cell Survival; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D015759:Ionomycin / Q000494:pharmacology; D051379:Mice; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000819:agonists*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D018832:Molecular Chaperones; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D015759:Ionomycin; D013755:Tetradecanoylphorbol Acetate