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The Ccr4-Not complex regulates TORC1 signaling and mitochondrial metabolism by promoting vacuole V-ATPase activity

ABSTRACT: The Ccr4-Not complex is an effector of multiple signaling pathways controlling gene transcription and mRNA turnover. Herein, we provide evidence that Ccr4-Not also activates nutrient signaling through the essential target of rapamycin complex 1 (TORC1) pathway. Mechanistically, Ccr4-Not loss decreases TORC1 signaling due to reduced stability of the vacuole V-ATPase that is required to activate TORC1 when associated with the Gtr1 GTPase containing EGO complex. Expressing a constitutively active Gtr1 in Ccr4-Not deficient cells bypasses the requirement for the V-ATPase and restores TORC1 signaling. Transcriptome analysis reveals that Ccr4-Not loss activates TORC1 repressed retrograde signaling to remodel metabolism and enhance mitochondrial function. Blocking retrograde signaling in a Ccr4-Not mutant further reduces TORC1 signaling, thus suggesting the enhanced mitochondrial metabolism due to Ccr4-Not loss is a metabolic adaptive response required to sustain TORC1 activity. Therefore, Ccr4-Not is a critical activator of TORC1 signaling that regulates cellular metabolism.

ORGANISM(S): Saccharomyces cerevisiae

PROVIDER: GSE138363 | GEO | 2019/10/04

REPOSITORIES: GEO

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The Ccr4-Not complex regulates TORC1 signaling and mitochondrial metabolism by promoting vacuole V-ATPase activity

Project description:The Ccr4-Not complex regulates TORC1 signaling and mitochondrial metabolism by promoting vacuole V-ATPase activity

| PRJNA575630 | ENA

V-ATPase/TORC1-mediated ATFS-1 translation directs mitochondrial UPR activation in C. elegans

Project description:To adapt mitochondrial function to the ever-changing intra- and extra-cellular environment, multiple mitochondrial stress response (MSR) pathways, including the mitochondrial unfolded protein response (UPRmt), have evolved. However, how the mitochondrial stress signal is sensed and relayed to UPRmt transcription factors, such as ATFS-1 in Caenorhabditis elegans, remains largely unknown. Here, we show that a panel of vacuolar H+-ATPase (v-ATPase) subunits and the target of rapamycin complex 1 (TORC1) activity are essential for the cytosolic relay of mitochondrial stress to ATFS-1, and for the induction of the UPRmt. Mechanistically, mitochondrial stress stimulates v-ATPase/Rheb-dependent TORC1 activation, subsequently promoting ATFS-1 translation. Increased translation of ATFS-1 upon mitochondrial stress furthermore relies on a set of ribosomal components, but is independent of GCN-2/PEK-1 signaling. Finally, the v-ATPase and ribosomal subunits are required for mitochondrial surveillance and mitochondrial stress-induced longevity. These results reveal a v-ATPase-TORC1-ATFS-1 signaling pathway that links mitochondrial stress to the UPRmt through intimate crosstalks between multiple organelles.

2022-09-23 | GSE179517 | GEO

Expression data from the liver of wild-type and Cnot3+/- mice: Fed vs Fasted

Project description:Decay of mRNAs initiates with shortening of the poly(A) tail. Although the CCR4-NOT complex participates in deadenylation, how it becomes activates remain obscure. We show that complete deficiency in CNOT3, subunit 3 of this complex, is lethal in mice, but that heterozygotes survive as lean mice with hepatic and adipose tissues containing reduced lipid levels. Cnot3+/- mice have enhanced metabolic rates and remain lean on high-fat diets. We further provide evidence suggesting that CNOT3, by changing its level in response to feeding conditions, affects the activity of the CCR4-NOT deadenylase against poly(A) tails of specific mRNAs coding for proteins involved in metabolism of carbohydrates and fats. Because the levels of CNOT3 protein were decreased under fasting conditions and increased upon refeeding and because CNOT3 could be a positive regulator of the CCR4-NOT deadenylase, we hypothesized that the levels of CCR4-NOT target mRNAs would be lower in fed mice than in fasted mice. We compared the gene expression profiles of fed and fasted wild-type mice. Microarray analysis revealed that approximately 1,200 mRNA transcripts were down-regulated in the livers of fed mice. Of these mRNAs, 68 corresponded to the genes up-regulated in the livers of Cnot3+/- mice and fasted wild-type mice. A large number of the 68 identified genes encoded proteins involved in metabolism, especially lipid metabolism and growth. The livers were isolated from 8-week-old fed wild-type, fasted wild-type and fasted Cnot3+/- mice (n = 2 for each genotype).

2011-12-09 | E-GEOD-18925 | biostudies-arrayexpress

Next Generation Sequencing Analysis of Maize Wild Type (WT) and thk1 Mutants Transcriptomes

Project description:The thk1 mutant, causing multiple aleurone layers, disrupts the NOT1 scaffolding subunit of the CCR4-NOT regulatory complex and dysregulates genes involved in cell division, signaling, differentiation and metabolism.

2020-07-29 | GSE155296 | GEO

Disruption of Cytochrome c Oxidase Function Induces Warburg Effect and Metabolic Reprogramming

Project description:Defects in mitochondrial oxidative phosphorylation complexes, altered bioenergetics and metabolic shift are often seen in cancers. Here we show a role for the dysfunction of electron transport chain component, cytochrome c oxidase (CcO) in cancer progression. We show that genetic silencing of the CcO complex by shRNA expression and loss of CcO activity in multiple cell types from the mouse and human sources resulted in metabolic shift to glycolysis, loss of anchorage dependent growth and acquired invasive phenotypes. Disruption of CcO complex caused loss of transmembrane potential and induction of Ca2+/Calcineurin-mediated retrograde signaling. Propagation of this signaling, includes activation of PI3-kinase, IGF1R and Akt, Ca2+ sensitive transcription factors and also, TGF1, MMP16, periostin that are involved in oncogenic progression. Whole genome expression analysis showed up regulation of genes involved in cell signaling, extracellular matrix interactions, cell morphogenesis, cell motility and migration. The transcription profiles reveal extensive similarity to retrograde signaling initiated by partial mtDNA depletion, though distinct differences are observed in signaling induced by CcO dysfunction. The possible CcO dysfunction as a biomarker for cancer progression was supported by data showing that esophageal tumors from human patients show reduced CcO subunits IVi1 and Vb in regions that were previously shown to be hypoxic core of the tumors. Our results show that mitochondrial electron transport chain defect initiates a retrograde signaling. These results suggest that a defect in CcO complex can potentially induce tumor progression. Total RNA from control and CcO IVi1 silenced cells was extract. Three independent samples were generated for control and silenced, respectively.

2015-05-05 | E-GEOD-68525 | biostudies-arrayexpress

State Transitions in the TORC1 Signaling Pathway and Information Processing in S. cerevisiae

Project description:TOR kinase complex I (TORC1) is a key regulator of cell growth and metabolism in all eukaryotes. Previous studies in yeast have shown that three GTPases, Gtr1, Gtr2 and Rho1, bind TORC1 in nitrogen and amino acid starvation conditions to block phosphorylation of the S6 kinase Sch9 and activate protein phosphatase 2A (PP2A). This leads to down-regulation of 450 Sch9-dependent protein and ribosome synthesis genes, and up-regulation of 100 PP2A-dependent nitrogen assimilation and amino acid synthesis genes. Here, using bandshift assays and microarray measurements, we show that the TORC1 pathway also populates three other stress/starvation states. First, in glucose starvation conditions, the AMP activated protein kinase (AMPK/Snf1) and at least one other factor, push the TORC1 pathway into an off state where Sch9- branch signaling and PP2A-branch signaling are both inhibited. Remarkably, the TORC1 pathway remains in the glucose starvation (PP2A off) state even when cells are simultaneously starved for nitrogen and glucose. Second, in osmotic stress, the MAPK Hog1/p38 drives the TORC1 pathway into a different Sch9 off, PP2A off state, where PP2A-branch signaling can still be activated by nitrogen starvation. Third, in oxidative stress and heat stress, TORC1-Sch9 signaling is blocked while weak PP2A-branch signaling occurs. Together, our data show that the TORC1 pathway acts an information-processing hub, activating different genes in different conditions to ensure that available energy is allocated to drive growth, amino acid synthesis or a stress response, depending on the needs of the cell.

2014-07-29 | GSE58992 | GEO

Exonuclease Xrn1 regulates TORC1 signaling in response to SAM availability

Project description:Autophagy is a conserved process of cellular self-digestion that promotes survival during nutrient stress. In yeast, methionine starvation is sufficient to induce autophagy. One pathway of autophagy induction is governed by the SEACIT complex, which regulates TORC1 activity in response to amino acids through the Rag GTPases Gtr1 and Gtr2 This work identifies an unexpected yet critical role for Xrn1 in nutrient sensing and growth control that extends beyond its canonical housekeeping function in RNA degradation and indicates an avenue for RNA metabolism to function in amino acid signaling into TORC1.

2023-10-19 | GSE226779 | GEO

Expression data from the liver of wild-type and Cnot3+/- mice: Fed vs Fasted

2011-12-09 | GSE18925 | GEO

Effect of Rh(III) on gene expression in HeLa cell line

Project description:We designed a highly emissive rhodium(III) complex ( Rh(III) complex) as the mtDNA intercalator. Rh(III) complex can specifically bind to mtDNA to cause the cytoplasmic release of mtDNA fragments to activate the cGAS-STING pathway. Moreover, Rh(III) complex activates the mitochondrial retrograde signaling by disturbing the key metabolites. Herein,we performed RNA-seq to illustrate the function of Rh(III) complex on HeLa cells. RNA-seq was performed on HeLa cells, which were treated by 1% DMSO or Rh(III) complex (1 uM, 6h), respectively.

2023-07-06 | GSE221227 | GEO

wild-type and gaf1 mutant cells treated with Torin1 or with a combination of caffeine/rapamycin

Project description:Target of Rapamycin Complex 1 (TORC1) signaling promotes growth and ageing. Inhibition of TORC1 leads to a down-regulation of factors that stimulate protein translation, which in turn contributes to longevity. TORC1-dependent post-transcriptional regulation of protein translation has been well studied, while analogous transcriptional regulation is less understood. Here we screened fission yeast deletion mutants for resistance to Torin1, which inhibits TORC1 and cell growth. Cells lacking the GATA transcription factor Gaf1 (gaf1Δ) grew normally even in high doses of Torin1. The gaf1Δ mutation shortened the chronological lifespan of non-dividing cells and diminished the longevity triggered by Torin1 treatment. Expression profiling and genome-wide binding experiments showed that, upon TORC1 inhibition, Gaf1 directly up-regulated genes for small-molecule metabolic pathways and indirectly repressed genes for protein translation. Surprisingly, Gaf1 bound to, and down-regulated the tRNA genes, so also functions as a transcription factor for genes transcribed by RNA polymerase III. Thus, Gaf1 controls the transcription of both coding and tRNA genes to inhibit translation and growth downstream of TORC1.

2020-03-02 | E-MTAB-8569 | biostudies-arrayexpress

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