eIF6 rebinding dynamically couples ribosome maturation and translation

DOI: 10.1038/s41467-022-29214-7

Authors: Pekka Jaako (Cambridge Institute for Medical Research; Wellcome Trust-Medical Research Council Stem Cell Institute; University of Cambridge School of Clinical Medicine; University of Gothenburg) , Alexandre Faille (Cambridge Institute for Medical Research; Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge) , Shengjiang Tan (Cambridge Institute for Medical Research; Wellcome Trust-Medical Research Council Stem Cell Institute; University of Cambridge School of Clinical Medicine) , Chi C. Wong (Cambridge Institute for Medical Research; Cambridge University Hospitals) , Norberto Escudero-Urquijo (Cambridge Institute for Medical Research; Wellcome Trust-Medical Research Council Stem Cell Institute; University of Cambridge School of Clinical Medicine) , Pablo Castro-Hartmann (Cambridge Institute for Medical Research; Wellcome Trust-Medical Research Council Stem Cell Institute; University of Cambridge School of Clinical Medicine) , Penny Wright (Cambridge University Hospitals) , Christine Hilcenko (Cambridge Institute for Medical Research; Wellcome Trust-Medical Research Council Stem Cell Institute; University of Cambridge School of Clinical Medicine) , David J. Adams (Wellcome Trust Sanger Institute) , Alan J. Warren (Cambridge Institute for Medical Research; Wellcome Trust-Medical Research Council Stem Cell Institute; University of Cambridge School of Clinical Medicine)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 13

State: Published (Approved)
Published: March 2022
Diamond Proposal Number(s): 22238

Abstract: 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.

Journal Keywords: Haematological diseases; Ribosome

Diamond Keywords: Shwachman-Diamond Syndrome (SDS)

Subject Areas: Biology and Bio-materials

Diamond Offline Facilities: Electron Bio-Imaging Centre (eBIC)
Instruments: Krios I-Titan Krios I at Diamond

Added On: 30/03/2022 10:04

Documents:
s41467-022-29214-7.pdf

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Structural biology Life Sciences & Biotech

Technical Tags:

Microscopy Electron Microscopy (EM) Cryo Electron Microscopy (Cryo EM)