Takano Shinichi, Ando Takashi, Hiramatsu Nobuhiko, Kanayama Asuka, Maekawa Shinya, Ohnuma Yuko, Enomoto Nobuyuki, Ogawa Hideoki, Paton Adrienne W, Paton James C, Kitamura Masanori, Nakao Atsuhito
Department of Immunology, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3898, Japan.
Biochem Biophys Res Commun. 2008 Jul 11;371(4):762-6. doi: 10.1016/j.bbrc.2008.04.132. Epub 2008 May 5.
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.
78 kDa葡萄糖调节蛋白（GRP78）是内质网（ER）中由各种应激诱导产生的一种重要分子伴侣。本研究表明，用抗CD3单克隆抗体、佛波酯（PMA）加离子霉素或抗原刺激可增加原代T细胞中GRP78 mRNA的水平，而这种增加被钙离子螯合剂乙二醇双四乙酸（EGTA）和1,2-双（2-氨基苯氧基）乙烷-N,N,N',N'-四乙酸四乙酰甲酯（BAPTA-AM）以及钙调神经磷酸酶抑制剂他克莫司（FK506）所抑制。此外，GRP78蛋白表达的特异性敲低诱导小鼠EL-4 T细胞系凋亡，这与C/EBP同源蛋白（CHOP）的诱导和半胱天冬酶-3（caspase-3）的激活相关。此外，GRP78的过表达抑制了PMA/离子霉素诱导的EL-4细胞死亡。总体而言，GRP78的表达通过钙依赖途径由T细胞受体（TCR）激活诱导产生，并且可能在维持T细胞在稳态和TCR激活状态下的活力中发挥关键作用。这些结果提示了GRP78在T细胞中的一种新的调节机制和重要功能。
