Molecular mechanisms of the ER stress-induced apoptosis and its inhibition by molecular chaperones

内质网应激途径是通过内质网中未折叠或错误折叠的蛋白质的积累来激活内质网以维持或恢复内质网功能。然而，当应激严重时，细胞凋亡途径被激活。CHOP是C/EBP家族的转录因子，参与内质网应激诱导的细胞凋亡。最近发现，同一通路在不同的应激条件下被激活，并参与了各种疾病的发病机制。然而，内质网应激诱导细胞凋亡的确切机制仍不清楚。在本研究中，我们发现在内毒素处理的小鼠的肺中，内质网应激-CHOP通路被激活。在CHOP基因敲除小鼠中，脂多糖诱导的炎症改变被抑制。因此，推测内质网应激-CHOP通路在内毒素诱导的炎症发病机制中起重要作用。骨髓瘤细胞产生大量的免疫球蛋白，并且内质网在骨髓瘤细胞中高度发达。因此，推测骨髓瘤细胞中的内质网应激通路被激活，将细胞从产生免疫球蛋白的负担中解救出来。转录因子XBP-1活性的诱导是内质网应激途径激活的标志。我们发现，在XBP-1活性形式阳性细胞的情况下，骨髓瘤来源的细胞系对内质网应激诱导的细胞凋亡具有抵抗力。我们还发现，在临床晚期的情况下，骨髓瘤细胞表达XBP-1活性形式。因此，XBP-1活性形式的表达可作为预后不良的良好标志物。我们目前正在研究CHOP诱导细胞凋亡的分子机制。

Endoplasmic reticulum (ER) stress pathway is activated by accumulation of unfolded or misfolded proteins in ER to maintain or recover ER functions. However, when stresses are severe, apoptosis pathway is activated. CHOP, a transcription factor of C/EBP family, is involved in ER stress-mediated apoptosis. Recently, it is found that same pathway is activated by various stresses, and is involved in the pathogenesis of various diseses. However, the precise mechanisms of the ER stress-mediated apoptosis are still unknown. In this study, we found that ER stress-CHOP pathway is activated in the lung of LPS-treated mice. LPS-induced inflammatory changes were suppressed in Chop knockout mice. Therefore, it is speculated that ER stress-CHOP pathway is crucial in the pathogenesis of LPS-induced inflammation.Myeloma cells produce huge amount of immunoglobulin, and ER is highly developed in myeloma cells. Therefore, it is speculated ER stress pathways are activated in myeloma cells to rescue cells from the burden of immunoglobulin production. Induction of transcription factor XBP-1 active form is a marker for the activation of ER stress pathway. We found that myeloma-derived cell lines are resistant to ER stress inducer-induced apoptosis in the case of XBP-1 active form positive cells. We also found that myeloma cells express XBP-1 active form in the case of advanced clinical stages. Therefore, the expression of XBP-1 active form can be a good marker of poor prognosis.We are now investigating the molecular mechanisms of CHOP-induced apoptosis.