PERK-ATAD3A interaction protects mitochondrial proteins synthesis during ER stress

Author:

Hughes Daniel T.ORCID,Brar Karinder K.,Morris Jordan L.,Subramanian Kelly,Krishna Shivaani,Gao Fei,Rieder Lara-Sophie,Freeman Joshua,Smith Heather L.,Jukes-Jones Rebekkah,Nunnari Jodi,Prudent Julien,Butcher Adrian J.,Mallucci Giovanna R.

Abstract

AbstractWidespread repression of protein synthesis rates is a key feature of Endoplasmic Reticulum (ER) stress, mediated by the ER sensor kinase PERK. While select transcripts escape this repression, global translational down-regulation impacts crucial protein levels in all cellular compartments, beyond the ER. How the cell manages this paradox is unclear. PERK has a unique cytoplasmic loop within its kinase domain that binds PERK’s target, eIF2α. We identified the mitochondrial protein, ATAD3A, as a new interactor of the loop, binding to a highly conserved region within it. During ER stress, increased interaction between ATAD3A and PERK attenuates PERK signalling to eIF2α, removing the translational block on several mitochondrial proteins. This occurs at novel context-dependent, mitochondria-ER contact sites. The interaction provides a previously unknown mechanism for fine-tuning translational repression at a local level, mitigating the impact of ER stress on mitochondria. Further, it represents a new target for selective modulation of PERK-eIF2α signalling in diseases from cancer to neurodegeneration.Graphical Abstract

Publisher

Cold Spring Harbor Laboratory

Cited by 4 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

1. The role of mitochondrial RNA association for mitochondrial homeostasis in neurons;Biochemical Journal;2024-01-29

2. Signaling plasticity in the integrated stress response;Frontiers in Cell and Developmental Biology;2023-12-07

3. ATAD3A: A Key Regulator of Mitochondria-Associated Diseases;International Journal of Molecular Sciences;2023-08-07

4. Role of Mitochondria–ER Contact Sites in Mitophagy;Biomolecules;2023-07-31

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