Trends in Genetics
Volume 34, Issue 11, November 2018, Pages 832-845
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Opinion
Pimp My Ribosome: Ribosomal Protein Paralogs Specify Translational Control

https://doi.org/10.1016/j.tig.2018.08.004Get rights and content

Highlights

Increasing evidence suggests that ribosome composition (both RNA and protein) plays an important role in the control of cell physiology.

Ribosome composition may be heterogeneous and ribosomes can be assembled from different core proteins, ribosome-associated proteins, and ribosomal RNAs – all of which are capable of undergoing chemical modification in vivo.

Specialized ribosomes may be defined by their ribosomal protein composition and appear to preferentially translate subsets of functionally related mRNAs to affect diverse cellular processes.

Ribosomal proteins may recognize sequence-specific elements or structures in mRNAs to control translation.

Loss of ribosome heterogeneity and/or ribosomal protein dysfunction affects the cellular proteome and can lead to human disease (ribosomopathies and cancer).

The ability of cells to grow and divide, differentiate and function, and even senesce is dependent on the fine-tuning of both gene and protein expression. Protein concentration in the cell is regulated not only at the transcriptional and post-translational levels, but also at the level of translation. Ribosomes, the molecular machines behind translation, were once considered to be an invariant driving force behind protein expression. However, studies over the past decade paint a rather different picture; namely, that ribosomes constitute an additional layer of regulatory control that might define which subsets of mRNAs are translated, to what extent, and to what purpose. Recent works summarized herein directly implicate ribosome heterogeneity and, in particular, ribosomal protein (RP) paralog specificity in regulating mRNA translation and control of the cellular translatome.

Section snippets

Defining Ribosome Heterogeneity

The cellular proteome can be highly diversified, especially in higher eukaryotes, to create vastly different cell types and accommodate different functions that can be responsive to the cellular environment. Ribosomes, extraordinarily complex multisubunit molecular machines comprising rRNA and RPs, translate the genetic code into polypeptides 1, 2, 3. While this protein factory has been the subject of intense study for decades, key questions remain regarding its direct role in the control of

RP Paralogs: Sibling Rivalry or Just Doing Their Own Thing?

Chromosome duplication early in eukaryote evolution and continued gene maintenance [13] is one reason why some RPs exist in paralog pairs in both lower and higher eukaryotes. However, for such pairs to have been maintained it has been proposed that individual isoforms might possess functional specificity and confer unique functions independent of their partner paralog (a.k.a. paralog specificity) 4, 7, 8, 9, 10, 14. Clues to the functional benefit of paralog specificity come from diverse

RP Paralog Specificity in Translational Control: New Evidence for Specialized Ribosomes

Numerous reviews have already compiled the wealth of evidence for RP specificity and potential for specialized ribosomes in Escherichia coli, yeast, Dictyostelium, Arabidopsis, zebrafish, and mice 4, 7, 8, 9, 10. In general, studies from the different organisms suggest that many RPs exist in discrete paralog pairs that show at least partial redundancy, in that cells remain viable on the loss or altered expression of one isoform, but since changes in isoform abundance may incur prominent

RAPs and Ribosome Targeting

In addition to canonical RPs that are incorporated into ribosomes during assembly, RAPs may associate with intact ribosomes, subunits, and perhaps specific RPs. Identified in earlier studies, RAPs include Reaper, RACK1/Asc1 (postulated to be a core RP), mTORC2, GYS1, fragile-X mental retardation protein (FMRP), and others. RAP interactions with ribosomes may expand their functional diversity and also allow the translational control of mRNA.

Barna and colleagues [34] performed a ribointeractome

Concluding Remarks: Future Directions and Considerations

The work of Silver and colleagues (2007) was perhaps the first in-depth demonstration that paralogous RPs can be functionally distinct and exhibit specific effects on gene expression [14]. While questions abound regarding the mechanism, the works described here further implicate RP specificity and, perhaps, RAPs in the translational control of subsets of mRNAs in eukaryotes 23, 24, 25, 34. Although it is clear that much more work remains (see Outstanding Questions), the studies presented here

Acknowledgments

Special thanks to Dr Anat Bashan (Department of Structural Biology, Weizmann Institute of Science), who was extremely helpful and generously created the schematic of the 80S ribosome in Figure 3. Thanks also to Drs Gal Haimovich and Nadav Segev for critical reading of the manuscript. J.E.G. holds the Besen-Brender Chair in Microbiology and Parasitology (Weizmann Institute of Science). This study was supported by a grant from the Kahn Center for Systems Biology (Weizmann Institute of Science).

Glossary

Internal ribosome entry site (IRES)
sequence element in the 5′UTR of an mRNA that confers translation initiation independent of the 5′ cap.
Paralog pairs
pairs of homologous genes that arose from a common ancestral sequence but have diverged within a species to yield proteins that may have different functions.
Pseudouridylation
the isomerization of uridine residues in RNA in which uracil is attached to the ribose moiety via a carbon–carbon bond. Pseudouridine incorporation into RNA can confer

References (48)

  • M. Kozak

    Point mutations define a sequence flanking the AUG initiator codon that modulates translation by eukaryotic ribosomes

    Cell

    (1986)
  • D. Simsek

    The mammalian ribo-interactome reveals ribosome functional diversity and heterogeneity

    Cell

    (2017)
  • A. Castello

    Insights into RNA biology from an atlas of mammalian mRNA-binding proteins

    Cell

    (2012)
  • A.G. Baltz

    The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts

    Mol. Cell

    (2012)
  • J. Kraut-Cohen et al.

    Addressing mRNAs to the ER: cis sequences act up!

    Trends Biochem. Sci.

    (2010)
  • R.P. Jansen

    mRNA transport meets membrane traffic

    Trends Genet.

    (2014)
  • D. Zabezhinsky

    An essential role for COPI in mRNA localization to mitochondria and mitochondrial function

    Cell Rep.

    (2016)
  • E. Thomson

    Eukaryotic ribosome biogenesis at a glance

    J. Cell Sci.

    (2013)
  • J.L. Woolford et al.

    Ribosome biogenesis in the yeast Saccharomyces cerevisiae

    Genetics

    (2013)
  • J. de la Cruz

    Functions of ribosomal proteins in assembly of eukaryotic ribosomes in vivo

    Annu. Rev. Biochem.

    (2015)
  • S. Xue et al.

    Specialized ribosomes: a new frontier in gene regulation and organismal biology

    Nat. Rev. Mol. Cell Biol.

    (2012)
  • K.E. Sloan

    Tuning the ribosome: the influence of rRNA modification on eukaryotic ribosome biogenesis and function

    RNA Biol.

    (2017)
  • T. von der Haar

    A quantitative estimation of the global translational activity in logarithmically growing yeast cells

    BMC Syst. Biol.

    (2008)
  • Z. Shi et al.

    Translating the genome in time and space: specialized ribosomes, RNA regulons, and RNA-binding proteins

    Annu. Rev. Cell Dev. Biol.

    (2015)
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