IRE1β is an ER stress sensor uniquely expressed in epithelial cells lining mucosal surfaces. Here, we show that intestinal epithelial cells expressing IRE1β have an attenuated unfolded protein response to ER stress. When modeled in HEK293 cells and with purified protein, IRE1β diminishes expression and inhibits signaling by the closely related stress sensor IRE1α. IRE1β can assemble with and inhibit IRE1α to suppress stress-induced XBP1 splicing, a key mediator of the unfolded protein response. In comparison to IRE1α, IRE1β has relatively weak XBP1 splicing activity, largely explained by a nonconserved amino acid in the kinase domain active site that impairs its phosphorylation and restricts oligomerization. This enables IRE1β to act as a dominant-negative suppressor of IRE1α and affect how barrier epithelial cells manage the response to stress at the host–environment interface.

中文翻译：

---

IRE1β 负向调节 IRE1α 信号以响应内质网应激

IRE1β 是一种内质网应激传感器，在粘膜表面的上皮细胞中独特表达。在这里，我们发现表达 IRE1β 的肠上皮细胞对 ER 应激的未折叠蛋白反应减弱。当在 HEK293 细胞中使用纯化蛋白进行建模时，IRE1β 会减少表达并抑制密切相关的应激传感器 IRE1α 的信号传导。IRE1β 可以与 IRE1α 组装并抑制 IRE1α，以抑制应激诱导的 XBP1 剪接，XBP1 剪接是未折叠蛋白反应的关键介质。与 IRE1α 相比，IRE1β 的 XBP1 剪接活性相对较弱，这主要是由于激酶结构域活性位点中的非保守氨基酸损害了其磷酸化并限制了寡聚化。这使得 IRE1β 能够充当 IRE1α 的显性失活抑制因子，并影响屏障上皮细胞如何管理对宿主-环境界面应激的反应。