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

Affiliations
  • 1Altos Labs, Cambridge Institute of Science, Granta Park, Cambridge CB21 6GP, UK.
  • 2UK Dementia Research Institute and Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 OAH, UK.
  • 3Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge CB2 0XY, UK.
  • 4Department of Molecular and Cellular Biology, University of California, Davis, Davis, CA 95616, USA.
  • 5Altos Labs, Bay Area Institute of Science, Redwood Shores, CA 94065, USA.
  • 6The Leicester van Geest MultiOmics Facility, Leicester LE1 9HN, UK.

Published on:

August 8, 2024

Abstract

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.

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