Psychiatry, Department of Integrated Medicine, Division of Internal Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.
Biochem Biophys Res Commun. 2011 Nov 25;415(3):519-25. doi: 10.1016/j.bbrc.2011.10.113. Epub 2011 Nov 3.
Sigma-1 receptors (Sig-1Rs) are the ER resident proteins. Sig-1Rs in the brain have been reported to be significantly reduced in patients with schizophrenia. The impediment of regulating Sig-1Rs expression levels increases the risk for schizophrenia. Thus elucidating the mechanism regulating Sig-1Rs expression might provide the strategy to prevent mental disorders. In this study, we have demonstrated that Sig-1Rs were transcriptionally upregulated by ATF4 in ER stress. Moreover, ATF4 directly bounds to the 5' flanking region of Sig-1R gene. The reporter activities using this region were enhanced in ER stress, or by ATF4 alone. The reporter activities with the pathogenic polymorphisms (GC-241-240TT, T-485A) were reduced. In addition, the processing of Caspase-4 was inhibited by Sig-1Rs. These results indicate that Sig-1Rs are transcriptionally upregulated via the PERK/eIF2α/ATF4 pathway and ameliolate cell death signaling. This study is the first report identifying the transcription factor regulating Sig-1Rs expression.
西格玛-1 受体（Sig-1Rs）是内质网驻留蛋白。有报道称，精神分裂症患者大脑中的 Sig-1Rs 显著减少。调节 Sig-1Rs 表达水平的障碍会增加患精神分裂症的风险。因此，阐明调节 Sig-1Rs 表达的机制可能为预防精神障碍提供策略。在这项研究中，我们已经证明，内质网应激时 ATF4 可转录上调 Sig-1Rs。此外，ATF4 可直接与 Sig-1R 基因的 5'侧翼区结合。该区域的报告基因活性在 ER 应激或 ATF4 单独作用下增强。具有致病性多态性（GC-241-240TT、T-485A）的报告基因活性降低。此外，Sig-1Rs 抑制 Caspase-4 的加工。这些结果表明，Sig-1Rs 通过 PERK/eIF2α/ATF4 通路转录上调，并减轻细胞死亡信号。本研究首次报道了调节 Sig-1Rs 表达的转录因子。
