Reduction in Ribosomal Protein Synthesis Is Sufficient To Explain Major Effects on Ribosome Production after Short-Term TOR Inactivation in <i>Saccharomyces cerevisiae</i>

Reiter, Alarich; Steinbauer, Robert; Philippi, Anja; Gerber, Jochen; Tschochner, Herbert; Milkereit, Philipp; Griesenbeck, Joachim

doi:10.1128/mcb.01227-10

Cited by 38 publications

(45 citation statements)

References 90 publications

(139 reference statements)

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“…The data obtained in this study suggest that inactivation of TOR not only stops the synthesis of new ribosomes, as previous studies have demonstrated (26,45,46), but also triggers extensive turnover of the existing ribosomes, resulting in a dramatic reduction of the cellular ribosome content. mediates accumulate after depletion of the core exosome subunit Rrp41 or the core-associated nuclease Dis3.…”

Section: Discussionsupporting

confidence: 77%

“…Previous studies found that the synthesis of new ribosomes stops within minutes after treatment of yeast cells with rapamycin (45,46). To investigate the fate of ribosomes remaining in cells after TOR inactivation, we performed quantitative assays to examine the rRNA contents in the common laboratory S. cerevisiae strain W303 before and after rapamycin treatment.…”

Section: Resultsmentioning

confidence: 99%

“…Ribosome synthesis in Saccharomyces cerevisiae is activated in response to favorable growth conditions, largely through TOR-regulated increases in rRNA transcription and the expression of genes encoding ribosomal proteins and assembly factors, termed the RP and Ribi regulons (4, 27, 38, 65). Conversely, inactivation of TOR causes repression of RP and Ribi gene expression and inhibits transcription and maturation of rRNAs (13,26,45,46,68), thereby causing an effective shutdown of ribosome biogenesis.In this study, we present evidence to suggest that TOR control of the cellular ribosome content extends beyond the regulation of new ribosome synthesis. Our data indicate that inactivation of TOR with rapamycin in growing yeast triggers a large-scale reduction of the ribosome content through the rapidly occurring turnover of the existing ribosomes.…”

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confidence: 99%

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Rapid Cytoplasmic Turnover of Yeast Ribosomes in Response to Rapamycin Inhibition of TOR

Pestov

Shcherbik

2012

Molecular and Cellular Biology

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The target of rapamycin (TOR) pathway is the central regulator of cell growth in eukaryotes. Inhibition of TOR by rapamycin elicits changes in translation attributed mainly to altered translation initiation and repression of the synthesis of new ribosomes. Using quantitative analysis of rRNA, we found that the number of existing ribosomes present in a Saccharomyces cerevisiae culture during growth in rich medium rapidly decreases by 40 to 60% when the cells are treated with rapamycin. This process is not appreciably affected by a suppression of autophagy, previously implicated in degradation of ribosomes in eukaryotes upon starvation. Yeast cells deficient in the exosome function or lacking its cytoplasmic Ski cofactors show an abnormal pattern of rRNA degradation, particularly in the large ribosomal subunit, and accumulate rRNA fragments after rapamycin treatment and during diauxic shift. The exosome and Ski proteins are thus important for processing of rRNA decay intermediates, although they are probably not responsible for initiating rRNA decay. The role of cytoplasmic nucleases in rapamycin-induced rRNA degradation suggests mechanistic parallels of this process to nutrient-controlled ribosome turnover in prokaryotes. We propose that ribosome content is regulated dynamically in eukaryotes by TOR through both ribosome synthesis and the cytoplasmic turnover of mature ribosomes.

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Section: Discussionsupporting

confidence: 77%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Rapid Cytoplasmic Turnover of Yeast Ribosomes in Response to Rapamycin Inhibition of TOR

Pestov

Shcherbik

2012

Molecular and Cellular Biology

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“…Processing of the 35S pre-rRNA occurs cotranscriptionally and is dependent on the presence of ribosomal proteins (Tschochner and Hurt 2003). The fast drop in RNA Pol I-dependent transcripts observed upon rapamycin treatment is apparently due to decreased translation (described above) of ribosomal proteins (Reiter et al 2011). The majority of mRNAs being translated in a rapidly growing cell encode ribosomal proteins (Warner 1999), and thus a drop in translation will rapidly reduce the levels of free ribosomal proteins that are themselves needed stoichiometrically for processing of rRNA into pre-ribosome particles.…”

Section: Tor Complexmentioning

confidence: 99%

Target of Rapamycin (TOR) in Nutrient Signaling and Growth Control

2011

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TOR (Target Of Rapamycin) is a highly conserved protein kinase that is important in both fundamental and clinical biology. In fundamental biology, TOR is a nutrient-sensitive, central controller of cell growth and aging. In clinical biology, TOR is implicated in many diseases and is the target of the drug rapamycin used in three different therapeutic areas. The yeast Saccharomyces cerevisiae has played a prominent role in both the discovery of TOR and the elucidation of its function. Here we review the TOR signaling network in S. cerevisiae.

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“…mTORC1 positively regulates many anabolic processes, with the role of mTORC1 signaling in translational initiation being the best understood. More recently a function of mTOR signaling in ribosome biogenesis has also been proposed (8)(9)(10)(11)(12). In particular, mTOR has been implicated in the control of RNA polymerase I transcription and rRNA processing.…”

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confidence: 99%

mTOR Signaling Regulates Nucleolar Targeting of the SUMO-Specific Isopeptidase SENP3

Raman

Nayak

2014

Molecular and Cellular Biology

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Ribosome biogenesis is a multistep cellular pathway that involves more than 200 regulatory components to ultimately generate translation-competent 80S ribosomes. The initial steps of this process, particularly rRNA processing, take place in the nucleolus, while later stages occur in the nucleoplasm and cytoplasm. One critical factor of 28S rRNA maturation is the SUMO-isopeptidase SENP3. SENP3 tightly interacts with the nucleolar scaffold protein NPM1 and is associated with nucleolar 60S preribosomes. A central question is how changes in energy supply feed into the regulation of ribosome maturation. Here, we show that the nutrient-sensing mTOR kinase pathway controls the nucleolar targeting of SENP3 by regulating its interaction with NPM1. We define an N-terminal domain in SENP3 as the critical NPM1 binding region and provide evidence that mTOR-mediated phosphorylation of serine/threonine residues within this region fosters the interaction of SENP3 with NPM1. The inhibition of mTOR triggers the nucleolar release of SENP3, thereby likely compromising its activity in rRNA processing. Since mTOR activity is tightly coupled to nutrient availability, we propose that this pathway contributes to the adaptation of ribosome maturation in response to the cellular energy status. Ribosomes are large ribonucleoprotein complexes functioning as molecular machines in protein synthesis. Mammalian 80S ribosomes are assembled from the small 40S and the large 60S subunit (1). The 60S subunit is composed of the 28S, the 5.8S, and the 5S rRNA and contains at least 46 ribosomal proteins, while the 40S subunit consists of around 30 ribosomal proteins and the 18S rRNA. The maturation of ribosomes is a highly regulated pathway that involves more than 200 nonribosomal proteins, commonly termed trans-acting factors (2, 3). Ribosome biogenesis is initiated in the nucleolus by RNA polymerase I (Pol I), transcribing a 47S precursor rRNA. This precursor is incorporated into a nucleolar 90S preribosomal particle, where specific bases in the rRNA are covalently modified and initial pre-RNA processing steps take place (4, 5). The 40S and 60S ribosomal subunits subsequently take a separate maturation pathway, which proceeds by a number of processing and remodelling events in the nucleolus and the nucleoplasm. Following export to the cytoplasm, both subunits are assembled to translation-competent 80S particles.As an integral part of protein synthesis, ribosome biogenesis must be tightly coupled to the energy status and nutrient levels of the cell. One key pathway that coordinates energy supply with protein translation is the mammalian target of rapamycin (mTOR) signaling network (6, 7). mTOR is an evolutionarily conserved serine/threonine kinase. In mammalian cells, mTOR is found in two distinct complexes, mTORC1 and mTORC2, that contain specific regulatory subunits and adaptor proteins. For example, Raptor and Rictor are the protein components involved in substrate recruitment and complex assembly of mTORC1 and mTORC2, respectively. mTORC1 positive...

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Reduction in Ribosomal Protein Synthesis Is Sufficient To Explain Major Effects on Ribosome Production after Short-Term TOR Inactivation in Saccharomyces cerevisiae

Cited by 38 publications

References 90 publications

Rapid Cytoplasmic Turnover of Yeast Ribosomes in Response to Rapamycin Inhibition of TOR

Rapid Cytoplasmic Turnover of Yeast Ribosomes in Response to Rapamycin Inhibition of TOR

Target of Rapamycin (TOR) in Nutrient Signaling and Growth Control

mTOR Signaling Regulates Nucleolar Targeting of the SUMO-Specific Isopeptidase SENP3

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