The unfolded protein response is a mechanism aiming at restoring endoplasmic reticulum (ER) homeostasis and is likely involved in other adaptive pathways. The unfolded protein response is transduced by three proteins acting as sensors and triggering downstream signaling pathways. Among them, inositol-requiring enzyme 1 alpha (IRE1α) (referred to as IRE1 hereafter), an endoplasmic reticulum–resident type I transmembrane protein, exerts its function through both kinase and endoribonuclease activities, resulting in both X-box binding protein 1 mRNA splicing and RNA degradation (regulated ire1 dependent decay). An increasing number of studies have reported protein–protein interactions as regulators of these signaling mechanisms, and additionally, driving other noncanonical functions. In this review, we deliver evolutive and structural insights on IRE1 and further describe how this protein interaction network (interactome) regulates IRE1 signaling abilities or mediates other cellular processes through catalytic-independent mechanisms. Moreover, we focus on newly discovered targets of IRE1 kinase activity and discuss potentially novel IRE1 functions based on the nature of the interactome, thereby identifying new fields to explore regarding this protein’s biological roles.

中文翻译：

---

探索 IRE1 相互作用组：从规范的信号传导功能到意想不到的作用

未折叠蛋白反应是一种旨在恢复内质网（ER）稳态的机制，并且可能涉及其他适应性途径。未折叠的蛋白质反应由三种蛋白质转导，这些蛋白质充当传感器并触发下游信号通路。其中，肌醇需求酶1α（IRE1α）（以下简称IRE1）是一种内质网驻留的I型跨膜蛋白，通过激酶和内切核糖核酸酶活性发挥其功能，产生X-box结合蛋白1 mRNA剪接和 RNA 降解（受调节的 ire1 依赖性衰变）。越来越多的研究报告蛋白质-蛋白质相互作用作为这些信号传导机制的调节剂，此外还驱动其他非规范功能。在这篇综述中，我们提供了关于 IRE1 的进化和结构见解，并进一步描述了这种蛋白质相互作用网络 (interactome) 如何通过催化独立机制调节 IRE1 信号传导能力或介导其他细胞过程。此外，我们关注新发现的 IRE1 激酶活性靶标，并根据相互作用组的性质讨论潜在的新 IRE1 功能，从而确定探索该蛋白质生物学作用的新领域。