eIF6 rebinding dynamically couples ribosome maturation and translation.
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Jaako, P., Faille, A., Tan, S., Wong, C. C., Escudero-Urquijo, N., Castro-Hartmann, P., Wright, P., et al. (2022). eIF6 rebinding dynamically couples ribosome maturation and translation.. Nat Commun, 13 (1) https://doi.org/10.1038/s41467-022-29214-7
Funder: Kay Kendall Leukaemia Fund
Funder: This work was supported by the Swedish Childhood Cancer Fund (PDS13/001, to PJ), the Swedish Research Council (2014-06807, to PJ), a Specialist Programme from Bloodwise (12048, to AJW), the UK Medical Research Council (MR/T012412/1, to AJW), European Cooperation in Science and Technology (COST) Action CA18233, “European Network for Innovative Diagnosis and treatment of Chronic Neutropenias, EuNet INNOCHRON” (to AJW), a Wellcome Trust strategic award to the Cambridge Institute for Medical Research (100140, to AJW), a core support grant from the Wellcome Trust and MRC to the Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, the Connor Wright Project, Ted’s Gang and the Cambridge National Institute for Health Research Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. A Wellcome Intermediate Fellowship (105914/Z/14/Z) and the Kay Kendall Leukaemia Fund (to CCW). We thank Dr. D. Y. Chirgadze for assistance with data collection at the Cryo-EM Facility, Department of Biochemistry, University of Cambridge, funded by the Wellcome Trust (206171/Z/17/Z; 202905/Z/16/Z), the Departments of Biochemistry and Chemistry, the Schools of Biological Sciences and Clinical Medicine and the University of Cambridge. We acknowledge Diamond Light Source for access and support of the cryo-EM facilities at the UK’s national Electron Bio-imaging Centre (eBIC) [under proposal EM BI22238], funded by the Wellcome Trust, MRC and BBRSC.
Protein synthesis is a cyclical process consisting of translation initiation, elongation, termination and ribosome recycling. The release factors SBDS and EFL1-both mutated in the leukemia predisposition disorder Shwachman-Diamond syndrome - license entry of nascent 60S ribosomal subunits into active translation by evicting the anti-association factor eIF6 from the 60S intersubunit face. We find that in mammalian cells, eIF6 holds all free cytoplasmic 60S subunits in a translationally inactive state and that SBDS and EFL1 are the minimal components required to recycle these 60S subunits back into additional rounds of translation by evicting eIF6. Increasing the dose of eIF6 in mice in vivo impairs terminal erythropoiesis by sequestering post-termination 60S subunits in the cytoplasm, disrupting subunit joining and attenuating global protein synthesis. These data reveal that ribosome maturation and recycling are dynamically coupled by a mechanism that is disrupted in an inherited leukemia predisposition disorder.
Article, /631/337/574/1789, /692/699/1541, /101/28, /64/24, /64/110, /13/31, article
Wellcome Trust (202905/Z/16/Z)
Wellcome Trust (206171/Z/17/Z)
Kay Kendall Leukaemia Fund (KKL1246)
Blood Cancer UK (21002)
External DOI: https://doi.org/10.1038/s41467-022-29214-7
This record's URL: https://www.repository.cam.ac.uk/handle/1810/335576