研究人员通过活细胞成像报道mRNA翻译的方式，意外发现内质网（ER）应激期间线粒体的活跃翻译得到了显著保护。线粒体蛋白ATAD3A与PERK相互作用，通过与PERK的靶点eIF2竞争结合，介导了这种对局部翻译的保护。
ER应激期间，PERK-ATAD3A相互作用增强，形成了线粒体与内质网的接触位点。此外，ATAD3A的结合减弱了局部PERK信号并恢复了一些线粒体蛋白的表达。因此，PERK-ATAD3A相互作用可以在亚细胞水平上调控翻译抑制，减轻ER应激对细胞的影响。
据介绍，ER应激会导致全细胞范围内的蛋白质合成抑制。由于难以在亚细胞水平上解析翻译速率，这种局部应激如何引发广泛抑制的机制尚不清楚。
附：英文原文
Title: PERK-ATAD3A interaction provides a subcellular safe haven for protein synthesis during ER stress
Author: Karinder K. Brar, Daniel T. Hughes, Jordan L. Morris, Kelly Subramanian, Shivaani Krishna, Fei Gao, Lara-Sophie Rieder, Sebastian Uhrig, Joshua Freeman, Heather L. Smith, Rebekkah Jukes-Jones, Edward Avezov, Jodi Nunnari, Julien Prudent, Adrian J. Butcher, Giovanna R. Mallucci
Issue&Volume: 2024-08-08
Abstract: Endoplasmic Reticulum (ER) stress induces repression of protein synthesis throughout the cell. Attempts to understand how localized stress leads to widespread repression have been limited by difficulties in resolving translation rates at the subcellular level. Here, using live-cell imaging of reporter mRNA translation, we unexpectedly found that during ER stress active translation at mitochondria was significantly protected. The mitochondrial protein, ATAD3A, interacted with PERK and mediated this effect on localized translation by competing for binding with PERK’s target, eIF2. PERK-ATAD3A interactions increased during ER stress, forming mitochondria-ER contact sites. Furthermore, ATAD3A binding attenuated local PERK signaling and rescued the expression of some mitochondrial proteins. Thus, PERK-ATAD3A interactions can control translational repression at a subcellular level, mitigating the impact of ER stress on the cell.
DOI: adp7114
Source: https://www.science.org/doi/10.1126/science.adp7114