Patterns of ribosomal protein expression specify normal and malignant human cells

Guimaraes, Joao C.; Zavolan, Mihaela

doi:10.1186/s13059-016-1104-z

Cited by 193 publications

(242 citation statements)

References 80 publications

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“…Other studies also report that RP perturbations can affect the translation of hundreds of genes organized in coherent functional groups [24,39]. RPs are routinely dysregulated in the context of cancer [36,40], and adjusted throughout cell growth and metabolic cycles [41]. Our measurements of differential RP stoichiometries of ribosomes isolated via sucrose gradients also suggest broader mRNA specificity [23].…”

mentioning

confidence: 65%

Ribosome stoichiometry: from form to function.

Emmott

Jovanović

Slavov

2018

Preprint

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The existence of eukaryotic ribosomes with distinct ribosomal protein (RP) stoichiometry and regulatory roles in protein synthesis been speculated for over sixty years. Recent advances in mass spectrometry and high throughput analysis have begun to identify and characterize distinct ribosome stoichiometry in yeast or mammalian systems. In addition to RP stoichiometry, ribosomes play host to a vast array of protein modifications, effectively expanding the number of human RPs from 80 to many thousands of distinct proteoforms. Is it possible these proteoforms combine to function as a 'ribosome code' to tune protein synthesis? We outline the specific benefits that translational regulation by specialized ribosomes can offer and discuss the means and methodologies available to correlate and characterize RP stoichiometry with function. We highlight previous research with a focus on formulating hypotheses that can guide future experiments and crack the 'ribosome code'.Ribosomes, the cellular machinery of protein synthesis, are present at up to ten million copies per cell in mammals. Despite their abundance and the wide array of known modifications to both ribosomal proteins (RPs) and rRNA, study of the direct role of the ribosome in tuning cellular translation has until recently taken a back seat to posttranscriptional regulation at the level of translation initiation. The hypothesis that ribosomes actively regulate protein synthesis as part of normal development and physiology dates back to the 1950s [1]. In the ensuing decades, numerous albeit inconclusive, observations have supported this hypothesis, and a subset of those are shown in Figure 1, color-coded by the type of evidence.For many years, the dominant 'abundance' model of translational regulation by the ribosome suggested a limited role for ribosomes in translation regulation [2]. In this model, if ribosomes have different initiation affinity for different transcripts, a global decrease in the availability of free ribosomes selectively decreases the initiation rates of different transcripts to varying degrees [2]. This mechanism, recently reviewed by Mills and Green [4], relies on the non-linear dependence of translation initiation on free ribosomes and applies quite generally. Indeed, recent research from the Sankaran lab suggested this mechanisms could explain the failure of erythroid lineage commitment seen with Diamond-Blackfan anaemia [5] 2 by the abundance model is limited in magnitude by the changes of total ribosomal content and in flexibility since it provides unidirectional regulation for all proteins.The concept of ribosome specialization In the 'specialized' ribosome model, ribosomes do not possess constant structure or composition (Figure 2A, B), and instead exhibit altered stoichiometry of what were previously thought to represent 'core' ribosomal proteins (Figure 1) [7,8]. In this model, different ribosomal compositions are functional and have specific roles in translation. Specialized ribosomes could co-exist within cells, or between ...

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confidence: 65%

Ribosome stoichiometry: from form to function.

Emmott

Jovanović

Slavov

2018

Preprint

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“…Mutations of other RPs have been linked to additional stem cell-specific defects (loss of body hair associated with mutations in RPL21 / eL21 (Zhou et al, 2011) and several human cancers, including T-cell acute lymphoblastic leukemia (T-ALL) (characterized by mutations in RPL5 / uL18 and RPL10 / uL16 within early T cell progenitors (De Keersmaecker et al, 2013)). Changes in RP transcript levels have also been observed among different cell and tissue types (Guimaraes and Zavolan, 2016; Kondrashov et al, 2011), suggesting that ribosomes may vary in composition. In fact, it is the tissues with high expression levels of Rpl38/eL38 transcripts that present with phenotypes in the haploinsufficient Rpl38/eL38 mouse model (Kondrashov et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Heterogeneous Ribosomes Preferentially Translate Distinct Subpools of mRNAs Genome-wide

et al. 2017

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Summary Emerging studies have linked the ribosome to more selective control of gene regulation. However, an outstanding question is whether ribosome heterogeneity at the level of core ribosomal proteins (RPs) exists and enables ribosomes to preferentially translate specific mRNAs genome-wide. Here, we measured the absolute abundance of RPs in translating ribosomes and profiled transcripts that are enriched or depleted from select subsets of ribosomes within embryonic stem cells. We find that heterogeneity in RP composition endows ribosomes with differential selectivity for translating subpools of transcripts including those controlling metabolism, cell cycle, and development. As an example, mRNAs enriched in binding to RPL10A/uL1-containing ribosomes are shown to require RPL10A/uL1 for their efficient translation. Within several of these transcripts, this level of regulation is mediated, at least in part, by internal ribosome entry sites. Together, these results reveal a critical functional link between ribosome heterogeneity and the post-transcriptional circuitry of gene expression.

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“…This was particularly the case of the ribosome structure and tRNA population. However, evidence has progressively accumulated showing a broad variation of the composition of the ribosomes (Sauert et al 2015;Guimaraes and Zavolan 2016;Sloan et al 2016) and of the tRNA populations in response to environmental signals, during differentiation and diseases.…”

Section: The State Of the Trna Population In The Cellmentioning

confidence: 99%

Protein folding and tRNA biology

2017

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Polypeptides can fold into tertiary structures while they are synthesized by the ribosome. In addition to the amino acid sequence, protein folding is determined by several factors within the cell. Among others, the folding pathway of a nascent polypeptide can be affected by transient interactions with other proteins, ligands, or the ribosome, as well as by the translocation through membrane pores. Particularly, the translation machinery and the population of tRNA under different physiological or adaptive responses can dramatically affect protein folding. This review summarizes the scientific evidence describing the role of translation kinetics and tRNA populations on protein folding and addresses current efforts to better understand tRNA biology. It is organized into three main parts, which are focused on: (i) protein folding in the cellular context; (ii) tRNA biology and the complexity of the tRNA population; and (iii) available methods and technical challenges in the characterization of tRNA pools. In this manner, this work illustrates the ways by which functional properties of proteins may be modulated by cellular tRNA populations.

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Patterns of ribosomal protein expression specify normal and malignant human cells

Cited by 193 publications

References 80 publications

Ribosome stoichiometry: from form to function.

Ribosome stoichiometry: from form to function.

Heterogeneous Ribosomes Preferentially Translate Distinct Subpools of mRNAs Genome-wide

Protein folding and tRNA biology

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