PERK-ATAD3A interaction protects mitochondrial proteins synthesis during ER stress

Hughes, D. T.; Brar, K. K.; Morris, J.; Subramanian, K.; Krishna, S.; Gao, F.; Rieder, L.-S.; Freeman, J. L.; Smith, H. L.; Jukes-Jones, R.; Nunnari, J.; Prudent, J.; Butcher, A. J.; Mallucci, G. R.

doi:10.1101/2022.07.24.501280

bioRxiv · 10.1101/2022.07.24.501280

PERK-ATAD3A interaction protects mitochondrial proteins synthesis during ER stress

Hughes, D. T.·Brar, K. K.·Morris, J.·Subramanian, K.·Krishna, S.·Gao, F.·Rieder, L.-S.·Freeman, J. L.·Smith, H. L.·Jukes-Jones, R.·Nunnari, J.·Prudent, J.·Butcher, A. J.·Mallucci, G. R.

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Abstract

Widespread 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 PERKs target, eIF2. 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 eIF2, 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-eIF2 signalling in diseases from cancer to neurodegeneration. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=153 HEIGHT=200 SRC="FIGDIR/small/501280v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@f74252org.highwire.dtl.DTLVardef@1234633org.highwire.dtl.DTLVardef@d5dc9aorg.highwire.dtl.DTLVardef@8606fe_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Hughes, D. T., Brar, K. K., Morris, J., Subramanian, K., Krishna, S., Gao, F., Rieder, L.-S., Freeman, J. L., Smith, H. L., Jukes-Jones, R., Nunnari, J., Prudent, J., Butcher, A. J., Mallucci, G. R.. 2022-07-24. PERK-ATAD3A interaction protects mitochondrial proteins synthesis during ER stress. https://doi.org/10.1101/2022.07.24.501280

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