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Localization of a TORC1-eIF4F translation complex during CD8+ T cell activation drives divergent cell fate

ABSTRACT: Activated CD8+ T lymphocytes differentiate into heterogeneous subsets. Using super-resolution imaging, we found that prior to the first division, dynein-dependent vesicular transport polarized active TORC1 towards the microtubule-organizing center (MTOC) at the proximal pole. This active TORC1 was physically associated with active eIF4F, required for the translation of c-myc mRNA. As a consequence, c-myc translating polysomes polarized toward the cellular pole proximal to the immune synapse, resulting in localized c-myc translation. Upon division, the TORC1-eIF4A complex preferentially sorted to the proximal daughter cell, facilitating asymmetric c-Myc synthesis. Transient disruption of eIF4A activity at first division skewed long-term cell fate trajectories to memory-like function. Using a genetic barcoding approach, we found that first-division sister cells often displayed differences in transcriptional profiles that largely correlated with c-Myc and TORC1 target genes. Our findings provide mechanistic insights as to how distinct T cell fate trajectories can be established during the first division.

ORGANISM(S): Mus musculus

PROVIDER: GSE196967 | GEO | 2022/04/24

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 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

Dynamic phosphoprotemics yeast nitrogen up-shift

Project description:To resolve the temporal sequence of phosphorylation events responding to nutritional and chemically induced up and downshifts of TORC1 signaling in S. cerevisiae wildtype, we performed quantitative MS phosphoproteomics upon nitrogen-quality up and downshifts and rapamycin treatment. We generated a high quality dataset byapplying a high resolution sampling, parallel sample processing and a dedicated data analysis pipeline that allowed us to select significant transient dynamics. By exploiting the temporal resolution of our data and the complementary of the shift experiments, we identified early phosphorylation changes regulated directly by TORC1 or by its proximal substrate kinases, and found both established and novel candidate TORC1 targets. Among the candidateTORC1 targets were the metabolic enzymes Amd1, Hom3, Nth1 and Tsl1, involved in nucleotide, amino acid and storage carbohydrate metabolism. Functional assessment of the role of phosphorylation for these and other enzymes was achieved by correlating phosphopeptide with the corresponding enzyme-associated metabolite dynamics. Candidate kinases regulating these enzymes were identified by establishing TORC1-proximity and differential kinase activity criteria. Our work provides first evidence of TORC1-dependent regulation of the metabolic enzymes Amd1and Hom3 by the kinases Sch9 and Atg1, respectively, providing mechanistic insights into on how TORC1 controls nucleotide and amino acid metabolism in response to the quality of the nitrogen source.

2022-02-22 | PXD000911 | Pride

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TORC1 signaling pathway inhibition by rapamycin and caffeine affect lifespan, global gene expression and cell proliferation of fission yeast

Project description:Target of rapamycin complex 1 (TORC1) is implicated in growth control and aging from yeast to humans. Fission yeast is emerging as a popular model organism to study TOR signaling, although rapamycin has been thought to not affect cell growth in this organism. Here we analyzed the effects of rapamycin and caffeine, singly and combined, on multiple cellular processes in fission yeast. The two drugs led to diverse and specific phenotypes that depended on TORC1 signaling pathway inhibition, including prolonged chronological lifespan, inhibition of global translation, inhibition of cell growth and division, and reprogramming of global gene expression mimicking nitrogen starvation. Rapamycin and caffeine differentially affected these various TORC1-dependent processes. Combined drug treatment augmented most phenotypes and effectively blocked cell growth. Although rapamycin showed a much more subtle effect on global translation than did caffeine, rapamycin was more effective in prolonging chronological lifespan. Rapamycin prolonged the lifespan of non-growing cells only when applied during the growth phase but not when applied after cells had stopped proliferation. The doses of rapamycin and caffeine strongly correlated with growth inhibition and with lifespan extension. This comprehensive analysis will inform future studies into TORC1 function and cellular aging in fission yeast and beyond.

2013-05-05 | E-MTAB-1489 | biostudies-arrayexpress

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Sch9 Is a Major Target of TORC1 in Saccharomyces cerevisiae

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2010-09-15 | E-GEOD-7660 | biostudies-arrayexpress

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Rocaglates convert DEAD-box protein eIF4A into a sequence-selective translational repressor

Project description:Rocaglamide A (RocA) typifies a class of protein synthesis inhibitors that selectively kill aneuploid tumor cells and repress translation of specific mRNAs. RocA targets eukaryotic initiation factor 4A (eIF4A), an ATP-dependent DEAD-box RNA helicase; its mRNA selectivity is proposed to reflect highly structured 5â² UTRs that depend strongly on eIF4A-mediated unwinding. However, rocaglate treatment may not phenocopy the loss of eIF4A activity, as these drugs actually increase the affinity between eIF4A and RNA. Here, we show that secondary structure in 5â² UTRs is only a minor determinant for RocA selectivity and RocA does not repress translation by reducing eIF4A availability. Rather, in vitro and in cells, RocA specifically clamps eIF4A onto polypurine sequences in an ATP-independent manner. This artificially clamped eIF4A blocks 43S scanning, leading to premature, upstream translation initiation and reducing protein expression from transcripts bearing the RocA-eIF4A target sequence. In elucidating the mechanism of selective translation repression by this lead anti-cancer compound, we provide an example of a drug stabilizing sequence-selective RNA-protein interactions. Bind-n-Seq and iCLIP-Seq

2016-06-15 | E-GEOD-79392 | biostudies-arrayexpress

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