Department of Cell Biology, Nanobiology Institute, Yale School of Medicine, Yale West Campus, West Haven, CT 06516, USA.
Department of Cell Biology, Nanobiology Institute, Yale School of Medicine, Yale West Campus, West Haven, CT 06516, USA.
Cell Rep. 2020 Dec 29;33(13):108563. doi: 10.1016/j.celrep.2020.108563.
Misfolded proteins in the endoplasmic reticulum (ER) activate IRE1α endoribonuclease in mammalian cells, which mediates XBP1 mRNA splicing to produce an active transcription factor. This promotes the expression of specific genes to alleviate ER stress, thereby attenuating IRE1α. Although sustained activation of IRE1α is linked to human diseases, it is not clear how IRE1α is attenuated during ER stress. Here, we identify that Sec63 is a subunit of the previously identified IRE1α/Sec61 translocon complex. We find that Sec63 recruits and activates BiP ATPase through its luminal J-domain to bind onto IRE1α. This leads to inhibition of higher-order oligomerization and attenuation of IRE1α RNase activity during prolonged ER stress. In Sec63-deficient cells, IRE1α remains activated for a long period of time despite the presence of excess BiP in the ER. Thus, our data suggest that the Sec61 translocon bridges IRE1α with Sec63/BiP to regulate the dynamics of IRE1α signaling in cells.
内质网（ER）中的错误折叠蛋白激活哺乳动物细胞中的 IRE1α 内切核酸酶，该酶介导 XBP1 mRNA 剪接以产生活性转录因子。这促进了特定基因的表达，从而减轻 ER 应激，从而减弱 IRE1α。尽管 IRE1α 的持续激活与人类疾病有关，但尚不清楚 ER 应激期间 IRE1α 如何减弱。在这里，我们确定 Sec63 是先前鉴定的 IRE1α/Sec61 易位体复合物的一个亚基。我们发现 Sec63 通过其腔内 J 结构域募集并激活 BiP ATP 酶，以与 IRE1α 结合。这导致在长时间 ER 应激期间抑制更高阶寡聚化和减弱 IRE1α 的核糖核酸酶活性。在 Sec63 缺陷细胞中，尽管 ER 中存在过量的 BiP，但 IRE1α 仍然长时间保持激活状态。因此，我们的数据表明 Sec61 易位体将 IRE1α 与 Sec63/BiP 桥接起来，以调节细胞中 IRE1α 信号转导的动态。
