Translating the Game: Ribosomes as Active Players

Abstract

Ribosomes have been long considered as executors of the translational program. The fact that ribosomes can control the translation of specific mRNAs or entire cellular programs is often neglected. Ribosomopathies, inherited diseases with mutations in ribosomal factors, show tissue specific defects and cancer predisposition. Studies of ribosomopathies have paved the way to the concept that ribosomes may control translation of specific mRNAs. Studies in Drosophila and mice support the existence of heterogeneous ribosomes that differentially translate mRNAs to coordinate cellular programs. Recent studies have now shown that ribosomal activity is not only a critical regulator of growth but also of metabolism. For instance, glycolysis and mitochondrial function have been found to be affected by ribosomal availability. Also, ATP levels drop in models of ribosomopathies. We discuss findings highlighting the relevance of ribosome heterogeneity in physiological and pathological conditions, as well as the possibility that in rate-limiting situations, ribosomes may favor some translational programs. We discuss the effects of ribosome heterogeneity on cellular metabolism, tumorigenesis and aging. We speculate a scenario in which ribosomes are not only executors of a metabolic program but act as modulators.

Keywords: RACK1; Shwachman-diamond syndrome; eIF6; metabolism; ribosomal proteins; ribosome heterogeneity; ribosomopathies.

FIGURE 1

Heat map representing relative gene expression levels in a cellular model for Shwachman Diamond Syndrome. We re-infected cells bearing the mutation R126T/R126T (corresponding to one of the most common mutations associated with Shwachman Diamond Syndrome) in the Sbds gene (Sbds^R126T/R126T MEFs) with either wild type Sbds (Sbds^RESCUE), or mock control (Sbds^MOCK). Heat map represents relative gene expression levels of genes associated with mitochondrial electron transport chain complex IV, showing an overall reduction in mutant Sbds^MOCK cells, indicating an impairment in ATP production. Heatmap is based on RNASeq raw data available at www.ebi.ac.uk/arrayexpress with accession number ID E-MTAB-5089, and analyzed in our previous work (Calamita et al., 2017).

FIGURE 2

A schematic model representing the list of genes whose mutations perturb ribosome machinery. The color indicates the associated phenotype, specified in ovals in the third row. In some cases, the effect is associated or supposed to be associated with extra-ribosomal functions of mutated genes (listed in squares in the fourth row). Briefly, alterations in ribosome biogenesis and/or mutations in ribosomal proteins are responsible for metabolic changes, abnormal cell cycle progression/cell growth, and selective translation. Ribosomal subunits adapted from 40S (Lomakin and Steitz, 2013) PDB code 5ANB to 60S (Weis et al., 2015) PDB code 4KZX. Orange color indicates the flux of alterations converging to metabolic defects, green color the flux converging to selective translation and blue color the one converging to altered cell cycle/cell growth. The exploration of effects of RP lesions on cell cycle, translation, and cell metabolism is a highly active area of research and novel effects of RP lesions still need to be discovered. ¹Danilova et al., 2011; ²Calamita et al., 2017; ³Angrisani et al., 2018; ⁴Ravera et al., 2016; ⁵Shi et al., 2017; ⁶In et al., 2016; ⁷Miller et al., 2004; ⁸Yoon et al., 2011; ⁹Li et al., 2016; ¹⁰Ceci et al., 2012; ¹¹Menne et al., 2007; ¹²Volarevic et al., 2000; ¹³Sulic et al., 2005; ¹⁴Dutt et al., 2011; ¹⁵Teng et al., 2013; ¹⁶Hermanto et al., 2002; ¹⁷Mamidipudi et al., 2004; ¹⁸Fei et al., 2017; ¹⁹Alawi and Lin, 2013; ²⁰Ge et al., 2010; ²¹Yao et al., 2016; ²²Badhai et al., 2009; ²³He et al., 2016; ²⁴Dai et al., 2004; ²⁵Yoon et al., 2006; ²⁶Li et al., 2012; ²⁷Stadanlick et al., 2011; ²⁸Kampen et al., 2018; ²⁹De Keersmaecker et al., 2013.