mTORC1 signaling controls multiple steps in ribosome biogenesis

Iadevaia, Valentina; Li, Rui; Proud, Christopher G.

doi:10.1016/j.semcdb.2014.08.004

Cited by 228 publications

(211 citation statements)

References 90 publications

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“…These effectors control protein synthesis by regulating cap-dependent translation of mRNAs, ribosome biogenesis and tRNA loading. 20,26,27 Since K-e-G-G MS/MS does not discriminate between poly-and monoubiquitinated sites, 17 detection of an enhanced ubiquitination implies either increased degradation of the target protein or changes in protein function. Our findings suggest that mRNA translation may be altered in OIS as a consequence of ubiquitination changes in several components of the translation machinery.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive analysis of the ubiquitinome during oncogene-induced senescence in human fibroblasts

Bengsch

Tang

et al. 2015

Cell Cycle

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Oncogene-induced senescence (OIS) is an important tumor suppression mechanism preventing uncontrolled proliferation in response to aberrant oncogenic signaling. The profound functional and morphological remodelling of the senescent cell involves extensive changes. In particular, alterations in protein ubiquitination during senescence have not been systematically analyzed previously. Here, we report the first global ubiquitination profile of primary human cells undergoing senescence. We employed a well-characterized in vitro model of OIS, primary human fibroblasts expressing oncogenic RAS. To compare the ubiquitinome of RAS-induced OIS and controls, ubiquitinated peptides were enriched by immune affinity purification and subjected to liquid chromatography tandem mass spectrometry (LC-MS/MS). We identified 4,472 ubiquitination sites, with 397 sites significantly changed (>3 standard deviations) in senescent cells. In addition, we performed mass spectrometry analysis of total proteins in OIS and control cells to account for parallel changes in both protein abundance and ubiquitin levels that did not affect the percentage of ubiquitination of a given protein. Pathway analysis revealed that the OIS-induced ubiquitinome alterations mainly affected 3 signaling networks: eIF2 signaling, eIF4/p70S6K signaling, and mTOR signaling. Interestingly, the majority of the changed ubiquitinated proteins in these pathways belong to the translation machinery. This includes several translation initiation factors (eIF2C2, eIF2B4, eIF3I, eIF3L, eIF4A1) and elongation factors (eEF1G, eEF1A) as well as 40S (RPS4X, RPS7, RPS11 and RPS20) and 60S ribosomal subunits (RPL10, RPL11, RPL18 and RPL35a). In addition, we observed enriched ubiquitination of aminoacyl-tRNA ligases (isoleucyl-, glutamine-, and tyrosine-tRNA ligase), which provide the amino acid-loaded tRNAs for protein synthesis. These results suggest that ubiquitination affects key components of the translation machinery to regulate protein synthesis during OIS. Our results thus point toward ubiquitination as a hitherto unappreciated regulatory mechanism during OIS.

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Section: Discussionmentioning

confidence: 99%

Comprehensive analysis of the ubiquitinome during oncogene-induced senescence in human fibroblasts

Bengsch

Tang

et al. 2015

Cell Cycle

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“…In yeast, transcriptional regulation of RP genes can involve mTOR and the transcription factor FHL-1, both of which are expressed in mammals. In contradistinction to yeast, human and murine RP genes are scattered throughout their genomes, and while there is evidence of coordinate regulation of these genes in response to various stimuli (e.g., 35, 55), how this transcriptional regulation is coordinated in mammals has yet to be determined (35) but is thought to be mTOR independent (37). For example, this set of genes is not affected in a microarray dataset when TSCϪ/Ϫ cells (which have a persistently activated mTOR complex 1 that BCAAs normally activate) are treated with rapamycin that would inhibit mTORC1 (19).…”

Section: Discussionmentioning

confidence: 99%

Global deletion ofBCATmincreases expression of skeletal muscle genes associated with protein turnover

Lynch

Kimball

et al. 2015

Physiological Genomics

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Lynch CJ, Kimball SR, Xu Y, Salzberg AC, Kawasawa YI. Global deletion of BCATm increases expression of skeletal muscle genes associated with protein turnover. Physiol Genomics 47: 569-580, 2015. First published September 8, 2015 doi:10.1152/physiolgenomics.00055.2015.-Consumption of a protein-containing meal by a fasted animal promotes protein accretion in skeletal muscle, in part through leucine stimulation of protein synthesis and indirectly through repression of protein degradation mediated by its metabolite, ␣-ketoisocaproate. Mice lacking the mitochondrial branched-chain aminotransferase (BCATm/Bcat2), which interconverts leucine and ␣-ketoisocaproate, exhibit elevated protein turnover. Here, the transcriptomes of gastrocnemius muscle from BCATm knockout (KO) and wildtype mice were compared by next-generation RNA sequencing (RNA-Seq) to identify potential adaptations associated with their persistently altered nutrient signaling. Statistically significant changes in the abundance of 1,486/ϳ39,010 genes were identified. Bioinformatics analysis of the RNA-Seq data indicated that pathways involved in protein synthesis [eukaryotic initiation factor (eIF)-2, mammalian target of rapamycin, eIF4, and p70S6K pathways including 40S and 60S ribosomal proteins], protein breakdown (e.g., ubiquitin mediated), and muscle degeneration (apoptosis, atrophy, myopathy, and cell death) were upregulated. Also in agreement with our previous observations, the abundance of mRNAs associated with reduced body size, glycemia, plasma insulin, and lipid signaling pathways was altered in BCATm KO mice. Consistently, genes encoding anaerobic and/or oxidative metabolism of carbohydrate, fatty acids, and branched chain amino acids were modestly but systematically reduced. Although there was no indication that muscle fiber type was different between KO and wild-type mice, a difference in the abundance of mRNAs associated with a muscular dystrophy phenotype was observed, consistent with the published exercise intolerance of these mice. The results suggest transcriptional adaptations occur in BCATm KO mice that along with altered nutrient signaling may contribute to their previously reported protein turnover, metabolic and exercise phenotypes.

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“…mTORC1 and c-MYC are potent inducers of ribosome biogenesis (27,28), and prior ChIP-Seq analyses indicated that NMP4 can bind to the promoter of the c-Myc gene (Fig. 1A) (20).…”

Section: Deletion Of Nmp4 In Mspcs Increases Ribosome Biogenesisgivenmentioning

confidence: 96%

Nuclear Matrix Protein 4 Is a Novel Regulator of Ribosome Biogenesis and Controls the Unfolded Protein Response via Repression of Gadd34 Expression

Young¹,

Shao

Bidwell

et al. 2016

Journal of Biological Chemistry

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The unfolded protein response (UPR) maintains protein homeostasis by governing the processing capacity of the endoplasmic reticulum (ER) to manage ER client loads; however, key regulators within the UPR remain to be identified. Activation of the UPR sensor PERK (EIFAK3/PEK) results in the phosphorylation of the ␣ subunit of eIF2 (eIF2␣-P), which represses translation initiation and reduces influx of newly synthesized proteins into the overloaded ER. As part of this adaptive response, eIF2␣-P also induces a feedback mechanism through enhanced transcriptional and translational expression of Gadd34 (Ppp1r15A), which targets type 1 protein phosphatase for dephosphorylation of eIF2␣-P to restore protein synthesis. Here we describe a novel mechanism by which Gadd34 expression is regulated through the activity of the zinc finger transcription factor NMP4 (ZNF384, CIZ). NMP4 functions to suppress bone anabolism, and we suggest that this occurs due to decreased protein synthesis of factors involved in bone formation through NMP4-mediated dampening of Gadd34 and c-Myc expression. Loss of Nmp4 resulted in an increase in c-Myc and Gadd34 expression that facilitated enhanced ribosome biogenesis and global protein synthesis. Importantly, protein synthesis was sustained during pharmacological induction of the UPR through a mechanism suggested to involve GADD34-mediated dephosphorylation of eIF2␣-P. Sustained protein synthesis sensitized cells to pharmacological induction of the UPR, and the observed decrease in cell viability was restored upon inhibition of GADD34 activity. We conclude that NMP4 is a key regulator of ribosome biogenesis and the UPR, which together play a central role in determining cell viability during endoplasmic reticulum stress.Professional secretory cells balance the synthesis, folding, and trafficking of proteins to ensure optimal protein export.Upon differentiation and physiological cues, increased synthesis of polypeptides slated for secretion can lead to accumulation of unfolded proteins in the endoplasmic reticulum (ER) 3 that trigger the unfolded protein response (UPR) (1). The UPR features multiple sensory proteins, including PERK (EIF2AK3/ PEK), IRE1 (ERN1), and ATF6, which are each situated in the ER and are activated by unfolded proteins in the ER (1). Induction of the UPR leads to a program of translational and transcriptional gene expression that collectively serve to expand the processing capacity of the ER to effectively manage an expanded ER client load (1).In response to ER stress, PERK phosphorylates the ␣ subunit of eIF2 (eIF2␣-P), which represses global translation initiation that reduces influx of newly synthesized proteins into the overloaded ER (2, 3). Coincident with dampening of global protein synthesis, eIF2␣-P leads to preferential translation of Atf4, encoding a transcription activator of UPR genes involved in nutrient import, metabolism, and alleviation of oxidative stress (4 -6). ATF4 also directly induces the transcriptional expression of Gadd34 (Ppp1r15A), which targets ty...

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mTORC1 signaling controls multiple steps in ribosome biogenesis

Cited by 228 publications

References 90 publications

Comprehensive analysis of the ubiquitinome during oncogene-induced senescence in human fibroblasts

Comprehensive analysis of the ubiquitinome during oncogene-induced senescence in human fibroblasts

Global deletion ofBCATmincreases expression of skeletal muscle genes associated with protein turnover

Nuclear Matrix Protein 4 Is a Novel Regulator of Ribosome Biogenesis and Controls the Unfolded Protein Response via Repression of Gadd34 Expression

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