Molecular mechanisms of neuronal death induced by endoplasmic reticulum stress.

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To study the molecular mechanisms underlying the endoplasmic reticulum(ER) stress response, we screened genes whose expression was induced during ER stress. We identified MDG1/ERdj4, a member of the DnaJ protein family, and OASIS, a member of CREB/ATF family. From the biological analyses, we demonstrated that MDG1/ERdj4 plays roles in stabilizing GRP78/BiP binding to unfolded substrate proteins in a J domain-dependent manner and preventing the accumulation of unfolded proteins in the ER. OASIS is cleaved at the membrane in response to ER stress and its cleaved N-terminal cytoplasmic domain, which contains the bZIP domain, translocates into the nucleus, and then activates transcription of target genes via direct binding to the ER stress responsive element 3, the ATF6 site and the cyclic AMP responsive element(CRE). Intriguingly, OASIS is induced at the transcriptional level during ER stress specifically in astrocytes of the central nervous system. These results reveal pivotal roles for OASIS in modulation of the astrocyte-specific unfolded protein response ; with possibilities that cell type-specific UPR signaling also exists in other cells.