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1.
EMBO J ; 36(6): 736-750, 2017 03 15.
Article in English | MEDLINE | ID: mdl-28242756

ABSTRACT

The inactivation of S6 kinases mimics several aspects of caloric restriction, including small body size, increased insulin sensitivity and longevity. However, the impact of S6 kinase activity on cellular senescence remains to be established. Here, we show that the constitutive activation of mammalian target of rapamycin complex 1 (mTORC1) by tuberous sclerosis complex (TSC) mutations induces a premature senescence programme in fibroblasts that relies on S6 kinases. To determine novel molecular targets linking S6 kinase activation to the control of senescence, we set up a chemical genetic screen, leading to the identification of the nuclear epigenetic factor ZRF1 (also known as DNAJC2, MIDA1, Mpp11). S6 kinases phosphorylate ZRF1 on Ser47 in cultured cells and in mammalian tissues in vivo Knock-down of ZRF1 or expression of a phosphorylation mutant is sufficient to blunt the S6 kinase-dependent senescence programme. This is traced by a sharp alteration in p16 levels, the cell cycle inhibitor and a master regulator of senescence. Our findings reveal a mechanism by which nutrient sensing pathways impact on cell senescence through the activation of mTORC1-S6 kinases and the phosphorylation of ZRF1.


Subject(s)
Aging , HSP40 Heat-Shock Proteins/metabolism , Protein Processing, Post-Translational , Ribosomal Protein S6 Kinases/metabolism , Animals , Cells, Cultured , DNA-Binding Proteins , Mice , Molecular Chaperones , Phosphorylation , RNA-Binding Proteins
2.
Mol Cell ; 46(1): 105-10, 2012 Apr 13.
Article in English | MEDLINE | ID: mdl-22424774

ABSTRACT

The target of rapamycin complex 1 (TORC1) is an essential regulator of eukaryotic cell growth that responds to growth factors, energy levels, and amino acids. The mechanisms through which the preeminent amino acid leucine signals to the TORC1-regulatory Rag GTPases, which activate TORC1 within the yeast EGO complex (EGOC) or the structurally related mammalian Rag-Ragulator complex, remain elusive. We find that the leucyl-tRNA synthetase (LeuRS) Cdc60 interacts with the Rag GTPase Gtr1 of the EGOC in a leucine-dependent manner. This interaction is necessary and sufficient to mediate leucine signaling to TORC1 and is disrupted by the engagement of Cdc60 in editing mischarged tRNA(Leu). Thus, the EGOC-TORC1 signaling module samples, via the LeuRS-intrinsic editing domain, the fidelity of tRNA(Leu) aminoacylation as a proxy for leucine availability.


Subject(s)
Leucine-tRNA Ligase/metabolism , Leucine/metabolism , Saccharomyces cerevisiae Proteins/metabolism , Saccharomyces cerevisiae/metabolism , Signal Transduction/physiology , Transcription Factors/metabolism , Leucine/genetics , Leucine-tRNA Ligase/genetics , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae Proteins/genetics , Transcription Factors/genetics
4.
Mol Cell ; 35(5): 563-73, 2009 Sep 11.
Article in English | MEDLINE | ID: mdl-19748353

ABSTRACT

The target of rapamycin complex 1 (TORC1) is a central regulator of eukaryotic cell growth that is activated by a variety of hormones (e.g., insulin) and nutrients (e.g., amino acids) and is deregulated in various cancers. Here, we report that the yeast Rag GTPase homolog Gtr1, a component of the vacuolar-membrane-associated EGO complex (EGOC), interacts with and activates TORC1 in an amino-acid-sensitive manner. Expression of a constitutively active (GTP-bound) Gtr1(GTP), which interacted strongly with TORC1, rendered TORC1 partially resistant to leucine deprivation, whereas expression of a growth inhibitory, GDP-bound Gtr1(GDP), caused constitutively low TORC1 activity. We also show that the nucleotide-binding status of Gtr1 is regulated by the conserved guanine nucleotide exchange factor (GEF) Vam6. Thus, in addition to its regulatory role in homotypic vacuolar fusion and vacuole protein sorting within the HOPS complex, Vam6 also controls TORC1 function by activating the Gtr1 subunit of the EGO complex.


Subject(s)
Adaptor Proteins, Vesicular Transport/metabolism , Guanine Nucleotide Exchange Factors/metabolism , Intracellular Membranes/enzymology , Monomeric GTP-Binding Proteins/metabolism , Protein Serine-Threonine Kinases/metabolism , Saccharomyces cerevisiae Proteins/metabolism , Saccharomyces cerevisiae/enzymology , Vacuoles/enzymology , Adaptor Proteins, Vesicular Transport/genetics , Amino Acid Transport Systems/metabolism , Amino Acids/metabolism , Cycloheximide/pharmacology , DNA-Binding Proteins/metabolism , Endosomes/enzymology , Guanine Nucleotide Exchange Factors/genetics , Guanosine Diphosphate/metabolism , Guanosine Triphosphate/metabolism , Intracellular Membranes/drug effects , Monomeric GTP-Binding Proteins/genetics , Multiprotein Complexes , Mutation , Protein Binding , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Synthesis Inhibitors/pharmacology , Protein Transport , Saccharomyces cerevisiae/drug effects , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae/growth & development , Saccharomyces cerevisiae Proteins/antagonists & inhibitors , Saccharomyces cerevisiae Proteins/genetics , Signal Transduction , Sirolimus/pharmacology , Time Factors , Transcription Factors/metabolism , Vacuoles/drug effects
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