Molecular mechanisms of neuronal death induced by endoplasmic reticulum stress.

为了研究内质网（ER）应激反应的分子机制，我们筛选了内质网应激诱导表达的基因。我们发现MDG1/ERdj4是DnaJ蛋白家族的成员，OASIS是CREB/ATF家族的成员。从生物学分析中，我们发现MDG1/ERdj4以J结构域依赖的方式稳定GRP78/BiP与未折叠底物蛋白的结合，并阻止未折叠蛋白在内质网中的积累。在内质网胁迫下，OASIS在细胞膜上被切割，其被切割的含有bZIP结构域的n端胞质结构域易位进入细胞核，然后通过直接结合内质网应激反应元件3、ATF6位点和环AMP反应元件（CRE）激活靶基因的转录。有趣的是，中枢神经系统星形胶质细胞在内质网应激时在转录水平上诱导OASIS。这些结果揭示了OASIS在星形胶质细胞特异性未折叠蛋白反应调节中的关键作用；细胞类型特异性UPR信号可能也存在于其他细胞中。

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.