內質網是個具有多功能的胞器，控制許多細胞內重要程序，包括：鈣離子恆定環境平衡、蛋白質合成、蛋白質運輸及細胞凋亡。當細胞處於生理或病理嚴重狀況下，鈣離子恆定環境平衡遭到破壞，造成未摺疊或錯誤摺疊的蛋白質堆積在內質網內腔導致內質網逆境，而且細胞會活化一系列訊號傳導路徑，統稱未摺疊蛋白質反應 (UPR)。其中一個UPR的特徵是內質網逆境蛋白質(葡萄糖調節蛋白質)的誘導表現。目前了解最清楚的是葡萄糖調節蛋白質七十八 (GRP78)，也是備為熟知的免疫球蛋白重鏈結合蛋白質又稱為BiP，具有調節鈣離子功能及執行其身為分子伴侶的任務，負責膜蛋白及分泌蛋白質的折疊。過去的報導指出GRP78會分佈於不同胞內位置，促使我們想要分析及比較當細胞遭遇內質網逆境，GRP78胞內分佈圖譜的改變，尤其是細胞在鈣離子平衡受到干擾狀況下造成的內質網逆境。
以離子誘導劑 (A23187) 或內質網鈣離子通道抑制劑 (TG) 處理細胞會導致內質網鈣離子濃度流失及細胞質濃度因而增加。利用共軛焦螢光顯微鏡及免疫螢光染色法，證明在正常細胞生長狀況下，GRP78 的免疫染色在細胞核附近的細胞質呈現顆粒分佈，也就是一般內質網的分佈圖譜。當細胞暴露於A23187或者TG藥物處理時，GRP78 免疫染色呈現較強的螢光訊號及遍佈於細胞質。另外，GRP78和粒線體染色明顯呈現位置重疊的蟲形絲線狀，暗示著GRP78與粒線體有共位情形，而這個現象可能是因為蛋白質目標導向之量的增加所導致。取得內質網逆境刺激的細胞粒線體之後，利用胞器分離及蛋白質酶分解實驗，得知有顯著量的GRP78會目標導向進入粒線體而且受粒線體膜的保護不受蛋白質酶的分解。利用穿透式電子顯微鏡觀察免疫金染色也再次證明GRP78於內質網及粒線體的超顯微分佈。當細胞處於內質網逆境狀況，GRP78大部分在粒線體內部且鑲飾於粒線體膜上。將粒線體進行細部結構分離，進一步發現GRP78主要座落在粒線體內外膜間腔、內膜及基質。利用放射線標示新合成蛋白質並接著進行胞器分離實驗，結果顯示當細胞遭遇內質網逆境，新合成的GRP78會目標導向進入粒線體。這些研究成果指出，在一些狀況下原本滯留於內質網的GRP78可以目標導向到粒線體，這可能是未摺疊蛋白質反應 (UPR) 在內質網及粒線體之間的訊號溝通。
我們也使用另一種內質網逆境刺激藥物，膠達那黴素 (geldamycin，GA) 來探討GRP78誘導表現所牽涉的訊號傳遞路徑。利用鈣離子監測，抑制劑篩選及活性氧檢測來觀察GA的細胞效應，結果顯示GA會開啟連續關聯的訊號路徑，連結丙型磷脂酵素 (phospholipase C, PLC)，使得細胞內鈣離子濃度增加，蛋白激酶C (protein kinase C, PKC) 活化及過氧自由基 (reactive oxygen species, ROS) 產生來誘導GRP78的表現。而且，從細胞外湧進的鈣離子、胞內儲存鈣離子變動及粒線體鈣濃度儲存對於GA所造成的鈣離子流通變化及GRP78的誘導表現扮演重要的角色。GA誘導GRP78表現的訊號傳遞可能說明了內質網逆境反應在細胞存活或細胞凋亡選擇過程的調節作用。

The endoplasmic reticulum (ER) is a multifunctional organelle controlling important cellular processes, including Ca2+ homeostasis, protein synthesis, protein trafficking, and apoptosis. Under physiologically or pharmacologically adverse conditions that perturb the calcium homeostasis, accumulation of unfolded or malfolded proteins in the ER lumen occurs, referred to as ER stress, and the cells will activate a series of signal transduction cascades collectively termed the unfolded protein response (UPR). One characteristic of the UPR is the induction of the ER resident stress proteins referred to as the glucose-regulated proteins (GRPs). The best characterized GRP78, also known as the immunoglobulin heavy chain binding protein or BiP, is thought to function in Ca2+ sequestration or as a molecular chaperone in the folding and assembly of membrane or secreted proteins. Previous reports of GRP78 in different cellular compartments prompted us to examine and compare the changes of GRP78 in intracellular distribution patterns in response to ER stress, specifically under calcium disturbance.
Treatment with calcium ionophore A23187 and sarcoplasmic/endoplasmic reticulum Ca2+ ATPase inhibitor thapsigargin (TG) results in a decrease of [Ca2+]er with a concurrent increase of [Ca2+]c. The immunostaining of GRP78 coupled with confocal microscopy demonstrated the granular and perinuclear expression as normal ER distribution in cells under normal growing conditions. When the cells were exposed to A23187 or TG, the greater proportion of GRP78 displayed a diffused distribution throughout the cytoplasm at a slightly higher intensity. Overlapping of GRP78 and mitochondria marker apparently depicted worm-shaped strings, suggesting that there is an increase in the level of colocalization and that this might occur from an increase in the level of targeting. Cellular fractionation and protease digestion of isolated mitochondria from ER-stressed cells suggested that a significant portion of GRP78 is localized to the mitochondria and is protease-resistant. Localizations of GRP78 in ER and mitochondria were confirmed by immunoelectron microscopy. In ER-stressed cells, GRP78 mainly localized within the mitochondria and decorated the mitochondrial membrane compartment. Submitochondrial fractionation studies further indicated that the mitochondrial resided GRP78 is mainly located in the intermembrane space, inner membrane, and matrix. Furthermore, radioactive labeling followed by subcellular fractionation showed that a significant portion of the newly synthesized GRP78 is localized to the mitochondria in cells under UPR. The results in this study indicate that, at least under certain circumstances, the ER resided chaperone GRP78 can be retargeted to mitochondria and thereby may be involved in correlating UPR signaling between these two organelles.
We also investigate the signaling pathway involved in the induction of GRP78 in cells under the treatment of geldanamycin (GA), which is a potent inducer of ER stress response. By using calcium monitoring, inhibitors screening and direct examination of the ROS contents rendered by GA, we show that GA exerts GRP78 inductive expression through a causative pathways connecting phospholipase C to intracellular calcium increase, PKC activation as well as ROS generation. Furthermore, the calcium influx from extracellular space, intracellular calcium store oscillations and mitochondrial calcium influx are important for the calcium mobilization and GRP78 expression induced by GA. The GA-induced GRP78 expression signaling cascades may represent regulation of the ER-stress response in cell survival or apoptotic program.

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