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

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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.