Heterogeneity and specialized functions of translation machinery: from genes to organisms

Abstract

Regulation of mRNA translation offers the opportunity to diversify the expression and abundance of proteins made from individual gene products in cells, tissues and organisms. Emerging evidence has highlighted variation in the composition and activity of several large, highly conserved translation complexes as a means to differentially control gene expression. Heterogeneity and specialized functions of individual components of the ribosome and of the translation initiation factor complexes eIF3 and eIF4F, which are required for recruitment of the ribosome to the mRNA 5′ untranslated region, have been identified. In this Review, we summarize the evidence for selective mRNA translation by components of these macromolecular complexes as a means to dynamically control the translation of the proteome in time and space. We further discuss the implications of this form of gene expression regulation for a growing number of human genetic disorders associated with mutations in the translation machinery.

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Fig. 1: Technologies for the quantification and characterization of translation machinery heterogeneity and functional specialization.
Fig. 2: Ribosome heterogeneity and specialization tune genetic networks.
Fig. 3: eIF3 is required for translation of specific cellular mRNAs.
Fig. 4: eIF4F specialization is regulated by cellular stimuli.

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Acknowledgements

The authors thank members of the Barna laboratory for thoughtful comments on this work. This work was supported by the New York Stem Cell Foundation NYSCF-R-I36 (M.B.), National Institutes of Health grant 1R01HD086634 (M.B.) and Pew Scholars Award (M.B.). N.R.G. is supported by National Science Foundation Graduate Research Fellowship DGE-114747. M.B. is a New York Stem Cell Foundation Robertson Investigator.

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Correspondence to Maria Barna.

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Nature Reviews Genetics thanks J. McCarthy, T. Preiss and the other, anonymous reviewer(s) for their contribution to the peer review of this work.

Glossary

Ribosome

The macromolecular machine that synthesizes proteins, consisting of a large (60S) and a small (40S) subunit that come together to form the translationally active eukaryotic 80S ribosome.

Start codon

The codon where translation is initiated, encoding the first amino acid of the peptide; typically an AUG encoding methionine.

Kozak sequence

The optimal sequence context for a start codon.

Open reading frame

(ORF). A region of mRNA, beginning with a start codon and ending with a stop codon, that has the capability of being translated into a peptide.

Core ribosomal protein

(RP). One of the 80 canonical RPs, which were originally identified by their high-affinity association with the ribosome.

Ribosomal RNA

(rRNA). The RNA components of the ribosome. Three eukaryotic rRNAs (5S, 5.8S and 28S) are in the large ribosomal subunit, while one (18S) is in the small subunit.

Expansion segments

Sections of ribosomal RNA (rRNA) that are longer in eukaryotes relative to prokaryotes. Many of these expansion segments also show growth between unicellular and multicellular organisms.

Untranslated region

(UTR). The portions of the mature mRNA that do not encode a protein. The sequence before the start codon is the 5′ UTR, while the section after the stop codon is the 3′ UTR.

Paralogues

Genes, typically created by a duplication event, with high homology to another gene within the same species.

Stoichiometry

The quantity of each constituent of a complex. If a subunit is not present on every complex, it is considered substoichiometric.

Polysomes

Multiple ribosomes that are translating the same mRNA transcript.

Proximity labelling

A technique to identify proteins in a subcellular region of interest. A promiscuous biotinylating enzyme is localized to a particular organelle or fused to a protein of interest and labels any proteins in its vicinity with biotin. Streptavidin pull-down and mass spectrometry can be used to identify these protein interactors.

Pseudogenes

A paralogue that can no longer be functionally expressed.

Internal ribosome entry sites

(IRESs). Regions in mRNA with the capability of initiating translation by recruiting translation machinery independently of a 5′ cap.

Ribosomopathies

Human diseases caused by ribosomal defects.

Diamond–Blackfan anaemia

(DBA). A common ribosomopathy caused by mutations in ribosomal proteins that results in anaemia and a variety of congenital birth defects.

Haploinsufficiency

When the expression of a gene from a single functional allele is not sufficient for normal cellular function.

5′ cap

A methylated guanine that is present at every 5′ end of all eukaryotic transcripts.

Preinitiation complex

(PIC). The ribosome and associated initiation factors that come together at specific stages of translation initiation. The eukaryotic 43S PIC contains the ribosome, eIF3, eIF2, eIF1, eIF1A and the initiator tRNA; the 48S PIC has the addition of eIF4F.

Translation efficiency

A measure of the rate of translation for a particular transcript of interest; typically calculated by normalizing ribosome occupancy to mRNA abundance.

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