PERK-ATAD3A interaction provides a subcellular safe haven for protein synthesis during ER stress

• 成果类型: Article
• 署名作者: Brar, Karinder K.; Hughes, Daniel T.; Morris, Jordan L.; Subramanian, Kelly; Krishna, Shivaani; Gao, Fei; Rieder, Lara-Sophie; Uhrig, Sebastian; Freeman, Joshua; Smith, Heather L.; Jukes-Jones, Rebekkah; Avezov, Edward; Nunnari, Jodi; Prudent, Julien; Butcher, Adrian J.; Mallucci, Giovanna R.
• 署名单位: University of Cambridge; University of Cambridge; University of Cambridge; UK Research & Innovation (UKRI); Medical Research Council UK (MRC); University of California System; University of California Davis
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-11801
• DOI: 10.1126/science.adp7114
• 发表日期: 2024-08-30
• 关键词: translation; perk; DYNAMICS

摘要

Endoplasmic reticulum (ER) stress induces the 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 ATPase family AAA domain-containing protein 3A (ATAD3A) interacted with protein kinase RNA-like endoplasmic reticulum kinase (PERK) and mediated this effect on localized translation by competing for binding with PERK's target, eukaryotic initiation factor 2 (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.