The Ccr4-Not complex regulates TORC1 signaling and mitochondrial metabolism by promoting vacuole V-ATPase activity
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ABSTRACT:
PROVIDER: PRJNA575630 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10224217.fastq.gz | Fastqsanger.gz | |||
| SRR10224218.fastq.gz | Fastqsanger.gz | |||
| SRR10224219.fastq.gz | Fastqsanger.gz | |||
| SRR10224220.fastq.gz | Fastqsanger.gz | |||
| SRR10224221.fastq.gz | Fastqsanger.gz |
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Project description: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.
2019-10-04 | GSE138363 | GEO
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
Project description:The Ccr4-Not complex functions as an effector of multiple signaling pathways that control gene transcription and mRNA turnover. Consequently, Ccr4-Not contributes to a diverse array of processes, which includes a significant role in cell metabolism. Yet a mechanistic understanding of how it contributes to metabolism is lacking. Herein, we provide evidence that Ccr4-Not activates nutrient signaling through the essential target of rapamycin complex 1 (TORC1) pathway. Ccr4-Not disruption reduces global TORC1 signaling, and it also upregulates expression of the cell wall integrity (CWI) pathway terminal kinase Mpk1. Although CWI signaling represses TORC1 signaling, we find that Ccr4-Not loss inhibits TORC1 independently of CWI activation. Instead, we demonstrate that Ccr4-Not promotes the function of the vacuole V-ATPase, which interacts with the Gtr1 GTPase-containing EGO complex to stimulate TORC1 in response to nutrient sufficiency. Bypassing the V-ATPase requirement in TORC1 activation using a constitutively active Gtr1 mutant fully restores TORC1 signaling in Ccr4-Not deficient cells. Transcriptome analysis and functional studies revealed that loss of the Ccr4 subunit activates the TORC1 repressed retrograde signaling pathway to upregulate mitochondrial activity. Blocking this mitochondrial upregulation in Ccr4-Not deficient cells further represses TORC1 signaling, and it causes synergistic deficiencies in mitochondrial-dependent metabolism. These data support a model whereby Ccr4-Not loss impairs V-ATPase dependent TORC1 activation that forces cells to enhance mitochondrial metabolism to sustain a minimal level of TORC1 signaling necessary for cell growth and proliferation. Therefore, Ccr4-Not plays an integral role in nutrient signaling and cell metabolism by promoting V-ATPase dependent TORC1 activation.
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Project description:V-ATPase/TORC1-mediated ATFS-1 translation directs mitochondrial UPR activation in C. elegans
| PRJNA744137 | ENA
Project description:To determine how TORC1 and PKA cooperate to regulate cell growth, we performed temporal analysis of gene expression in yeast switched from a non-fermentable substrate, to glucose, in the presence and absence of TORC1 and PKA inhibitors. Quantitative analysis of these data reveals that PKA drives the expression of key cell growth genes during transitions into, and out of, the rapid growth state in glucose, while TORC1 is important for the steady-state expression of the same genes.
2019-07-19 | GSE133591 | GEO
Project description:The Target Of Rapamycin (TOR) protein is a Ser/Thr kinase that functions in two distinct multiprotein complexes: TORC1 and TORC2. These conserved complexes regulate many different aspects of cell growth in response to intra- and extracellular cues. Here we report the first bona fide substrate of yeast TORC1: the AGC-kinase Sch9. Six amino acids in the c-terminus of Sch9 are directly phosphorylated by TORC1. Phosphorylation of these residues is lost upon rapamycin-treatment as well as carbon- or nitrogen-starvation and transiently reduced following application of osmotic, oxidative or thermal stress. TORC1-dependent phosphorylation is required for Sch9 activity and replacement of residues phosphorylated by TORC1 with Asp/Glu renders Sch9 activity TORC1-independent. Sch9 is required for TORC1 to properly regulate ribosome biogenesis, translation initiation and entry into G0 phase, but not expression of Gln3-dependent genes. Our results suggest that Sch9 functions analogously to the mammalian TORC1 substrate S6K1 rather than the mTORC2 substrate PKB/Akt. Keywords: time course, cell type.
2007-04-28 | GSE7660 | GEO
Project description:The Target Of Rapamycin (TOR) protein is a Ser/Thr kinase that functions in two distinct multiprotein complexes: TORC1 and TORC2. These conserved complexes regulate many different aspects of cell growth in response to intra- and extracellular cues. Here we report the first bona fide substrate of yeast TORC1: the AGC-kinase Sch9. Six amino acids in the c-terminus of Sch9 are directly phosphorylated by TORC1. Phosphorylation of these residues is lost upon rapamycin-treatment as well as carbon- or nitrogen-starvation and transiently reduced following application of osmotic, oxidative or thermal stress. TORC1-dependent phosphorylation is required for Sch9 activity and replacement of residues phosphorylated by TORC1 with Asp/Glu renders Sch9 activity TORC1-independent. Sch9 is required for TORC1 to properly regulate ribosome biogenesis, translation initiation and entry into G0 phase, but not expression of Gln3-dependent genes. Our results suggest that Sch9 functions analogously to the mammalian TORC1 substrate S6K1 rather than the mTORC2 substrate PKB/Akt. Keywords: time course, cell type. Global transcriptional analysis of rapamycin response was conducted on cells expressing either a wild-type, Sch9(WT), or TOR-independent allele of Sch9, Sch9(2D3E). Reference samples used were cells collected immediately prior to rapamycin treatment for the respective cell genotypes. Test samples were collected 20, 30, 60, 90, 120, and 180min post rapamycin treatment.
2010-09-15 | E-GEOD-7660 | biostudies-arrayexpress
Project description:Wild type, ccr4∆, ccr4∆ pbp1∆ cells were grown in YPD medium from log phase to stationary phase. Total RNAs ere extracted and subjected to microarray analysis.
2022-03-18 | GSE198743 | GEO
Project description:Snf1 and TORC1 are two global regulators that sense the nutrient availability and regulate the cell growth in yeast Saccharomyces cerevisiae. Here we undertook a systems biology approach to study the effect of deletion of these genes and investigate the interaction between Snf1 and TORC1 in regulation of gene expression and cell metabolism.
2011-10-20 | GSE24421 | GEO
Project description:The centromere is a pivotal chromatin domain that ensures accurate chromosome segregation during cell division. However, the epigenome regulation of the centromere and its impact on centromere function remain largely elusive. Here in the model plant Arabidopsis, we show that CCR4, the catalytic subunit of the RNA deadenylation complex CCR4-NOT, is essential for maintenance of the centromere epigenome and chromosome integrity. We demonstrate that CCR4 is involved in shortening of the poly(A) tails of transcripts originated from centromeric transposons and repeats, thereby promoting the production of small interfering RNAs (siRNAs). The CCR4-dependent siRNAs guide non-CG DNA methylation at centromere repeats, and CCR4 cooperates with canonical DNA methylation pathways to enhance centromeric H3K9 methylation and ensure mitotic chromosome stability. Our study illustrates the crucial role of RNA quality control in RNA interference and reveals the elaborate mechanism that safeguards plant centromeres through epigenomic regulation.
2024-08-24 | GSE274196 | GEO