eIF6 rebinding dynamically couples ribosome maturation and translation

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 leukaemia 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. Here, we show 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. Our data reveal that ribosome maturation and recycling are dynamically coupled by a mechanism that is disrupted in an inherited leukaemia predisposition disorder.

The role of genetic factors in different outcomes of pediatric myelodysplastic syndromes

“…[21] This probably brings about a reduced dose of EIF6 in SBDS-de cient HSPCs, which may help bypass the restraint on growth by ameliorating the defect in ribosomal subunit joining, in turn favouring the formation of actively translating 80S ribosomes and provide a clonal tness advantage. [21][22][23][24] This mechanism probably underlie the stable clinical course of case 2. The exploration of this mechanism provides insight for the treatment of other SDS patients without del20q.…”