Guo Jinbai, Polymenis Michael
Department of Biochemistry & Biophysics, Texas A&M University, 2128 TAMU, College Station, Texas 77843, USA.
EMBO Rep. 2006 Nov;7(11):1124-7. doi: 10.1038/sj.embor.7400813. Epub 2006 Sep 22.
Accumulation of unfolded proteins in the endoplasmic reticulum triggers the unfolded protein response (UPR). How the UPR is downregulated is not well understood. Inositol requirement 1 (Ire1) is an endoplasmic reticulum transmembrane UPR sensor in Saccharomyces cerevisiae. When the UPR is triggered, Ire1 is autophosphorylated, on Ser 840 and Ser 841, inducing the cytosolic endonuclease activity of Ire1, thereby initiating the splicing and translational de-repression of HAC1 mRNA. Homologous to Atf/Creb1 (Hac1) activates UPR transcription. Here, we report that the dose-dependent cell-cycle regulator 2 (Dcr2) phosphatase functionally and physically interacts with Ire1. We identified genetic interactions between DCR2 and genes, including IRE1, which are involved in secretory processes. Overexpression of DCR2, but not of a catalytically inactive DCR2 allele, significantly delays HAC1 splicing and sensitizes cells to the UPR. Furthermore, Dcr2 physically interacts in vivo with Ire1-S840E,S841E, which mimics phosphorylated Ire1, and Dcr2 de-phosphorylates Ire1 in vitro. Our results are consistent with de-phosphorylation of Ire1 being a mechanism for antagonizing UPR signalling.
内质网中未折叠蛋白的积累会触发未折叠蛋白反应（UPR）。目前对UPR如何被下调还了解甚少。肌醇需求蛋白1（Ire1）是酿酒酵母中的一种内质网跨膜UPR传感器。当触发UPR时，Ire1在丝氨酸840和丝氨酸841处发生自磷酸化，诱导Ire1的胞质核酸内切酶活性，从而启动HAC1 mRNA的剪接和翻译去抑制。与Atf/Creb1同源（Hac1）激活UPR转录。在此，我们报道剂量依赖性细胞周期调节因子2（Dcr2）磷酸酶在功能和物理上与Ire1相互作用。我们确定了DCR2与包括IRE1在内的参与分泌过程的基因之间的遗传相互作用。过量表达DCR2，但不表达催化失活的DCR2等位基因，会显著延迟HAC1的剪接并使细胞对UPR敏感。此外，Dcr2在体内与模拟磷酸化Ire1的Ire1-S840E、S841E发生物理相互作用，并且Dcr2在体外使Ire1去磷酸化。我们的结果与Ire1的去磷酸化是拮抗UPR信号传导的一种机制相一致。
