武汉大学Yong Liu小组取得一项新突破。他们的最新研究发现哺乳动物IRE1α与应激颗粒在动态和功能上结合。相关论文于2024年5月7日发表在《自然-细胞生物学》杂志上。

研究人员发现在哺乳动物细胞中，IRE1α集群的形成是与应激颗粒（SGs）的组装相耦合的内质网（ER）膜相分离事件。针对不同的应激源，IRE1α簇会动态地与ER上的SG相连。IRE1α的细胞膜连接体部分具有内在无序区，对其与SG的凝聚至关重要。

此外，SG组装的破坏会消除IRE1α的聚合，并影响XBP1 mRNA的剪接，而这种IRE1α-SG的聚合会在ER应激期间使促进已有IRE1α-XBP1通路的生化成分富集。该发现揭示了IRE1α-SG凝聚体在时空组装过程中的相分离机制，从而提高了IRE1α的效率和应激处理能力。

研究人员表示，ER应激时，ER驻留跨膜蛋白激酶/内切酶肌醇需要酶1（IRE1）通过转录因子X-box结合蛋白1（XBP1s）的非典型剪接是启动未折叠蛋白反应（UPR）的一个关键分支。活化的IRE1可以形成大的集群/病灶，但其确切的动态结构和功能特性在很大程度上仍然未知。

附：英文原文

Title: Mammalian IRE1α dynamically and functionally coalesces with stress granules

Author: Liu, Songzi, Zhang, Xiaoge, Yao, Xin, Wang, Guan, Huang, Shijia, Chen, Peng, Tang, Mingliang, Cai, Jie, Wu, Zhuyin, Zhang, Yiliang, Xu, Rongzhi, Liu, Kai, He, Kangmin, Wang, Yan, Jiang, Lei, Wang, Qiong A., Rui, Liangyou, Liu, Jianmiao, Liu, Yong

Issue&Volume: 2024-05-07

Abstract: Upon endoplasmic reticulum (ER) stress, activation of the ER-resident transmembrane protein kinase/endoribonuclease inositol-requiring enzyme 1 (IRE1) initiates a key branch of the unfolded protein response (UPR) through unconventional splicing generation of the transcription factor X-box-binding protein 1 (XBP1s). Activated IRE1 can form large clusters/foci, whose exact dynamic architectures and functional properties remain largely elusive. Here we report that, in mammalian cells, formation of IRE1α clusters is an ER membrane-bound phase separation event that is coupled to the assembly of stress granules (SGs). In response to different stressors, IRE1α clusters are dynamically tethered to SGs at the ER. The cytosolic linker portion of IRE1α possesses intrinsically disordered regions and is essential for its condensation with SGs. Furthermore, disruption of SG assembly abolishes IRE1α clustering and compromises XBP1 mRNA splicing, and such IRE1α–SG coalescence engenders enrichment of the biochemical components of the pro-survival IRE1α–XBP1 pathway during ER stress. Our findings unravel a phase transition mechanism for the spatiotemporal assembly of IRE1α–SG condensates to establish a more efficient IRE1α machinery, thus enabling higher stress-handling capacity.

DOI: 10.1038/s41556-024-01418-7

Source: https://www.nature.com/articles/s41556-024-01418-7