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Haematologica 2021 Volume 106(3):746-758
Red Cell Biology and its Disorders
Integrated analyses of translatome and proteome identify the rules of translation selectivity in RPS14-deficient cells
Ismael Boussaid,1 Salomé Le Goff,1,2,* Célia Floquet,1,* Emilie-Fleur Gautier,1,3 Anna Raimbault,1 Pierre-Julien Viailly,4 Dina Al Dulaimi,1 Barbara Burroni,5 Isabelle Dusanter-Fourt,1 Isabelle Hatin,6 Patrick Mayeux,1,2,3,#
Bertrand Cosson7,# and Michaela Fontenay1,2,3,4,8
1Université de Paris, Institut Cochin, CNRS UMR 8104, INSERM U1016, Paris; 2Laboratoire d’Excellence du Globule Rouge GR-Ex, Université de Paris, Paris; 3Proteomic Platform 3P5, Université de Paris, Paris; 4Centre Henri-Becquerel, Institut de Recherche et d’Innovation Biomedicale de Haute Normandie, INSERM U1245, Rouen; 5Assistance Publique-Hôpitaux de Paris, Centre-Université de Paris - Cochin, Service de Pathologie, Paris; 6Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Université de Paris-Sud, Université Paris-Saclay, Gif-sur-Yvette Cedex; 7Université de Paris, Epigenetics and Cell Fate, CNRS UMR 7216, Paris and 8Assistance Publique- Hôpitaux de Paris, Centre-Université de Paris - Hôpital Cochin, Service d’Hématologie Biologique, Paris, France
*SLG and CF contributed equally to this work.
#PM and BC contributed equally as co-senior authors.
ABSTRACT
In ribosomopathies, the Diamond-Blackfan anemia (DBA) or 5q- syn- drome, ribosomal protein (RP) genes are affected by mutation or deletion, resulting in bone marrow erythroid hypoplasia. Unbalanced production of ribosomal subunits leading to a limited ribosome cellular content regu- lates translation at the expense of the master erythroid transcription factor GATA1. In RPS14-deficient cells mimicking 5q- syndrome erythroid defects, we show that the transcript length, codon bias of the coding sequence (CDS) and 3’UTR (untranslated region) structure are the key determinants of trans- lation. In these cells, short transcripts with a structured 3’UTR and high codon adaptation index (CAI) showed a decreased translation efficiency. Quantitative analysis of the whole proteome confirmed that the post-tran- scriptional changes depended on the transcript characteristics that governed the translation efficiency in conditions of low ribosome availability. In addi- tion, proteins involved in normal erythroid differentiation share most deter- minants of translation selectivity. Our findings thus indicate that impaired erythroid maturation due to 5q- syndrome may proceed from a translational selectivity at the expense of the erythroid differentiation program, and sug- gest that an interplay between the CDS and UTR may regulate mRNA trans- lation.
Introduction
A haploinsufficiency or mutation of ribosomal protein (RP) genes causes alter- ations in the ribosome’s translation capacity; these disorders are known as “riboso- mopathies”. Diamond-Blackfan anemias (DBA) are provoked by heterozygous loss- of-function mutations in one of 18 different RP genes,1 whilst the haploinsufficiency of the RPS14 gene accounts for the erythroid phenotype in 5q- syndrome.2,3 In these diseases, the bone marrow (BM) erythroid lineage is commonly hypoplastic and this has prompted the search for the mechanisms underlying specific dysregulation of translation. Several models have been proposed to explain the observed pheno- types in ribosomopathies.4 In one model, changes in the cellular ribosome concen- tration relative to mRNA levels may cause changes in the translation efficiency of different classes of transcripts due to the competition for ribosomes among the cel- lular mRNA content.4 In a second model, specialized ribosomes with a modified RP composition, or with RP or rRNA modifications, could be responsible for changes
Correspondence:
MICHAELA FONTENAY
michaela.fontenay@inserm.fr
Received: October 7, 2019. Accepted: March 26, 2020. Pre-published: April 23, 2020.
https://doi.org/10.3324/haematol.2019.239970
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