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

by Hongfeng Chen, P. Winston Miller, Daniel L. Johnson, R. Nicholas Laribee

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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Paper source
Plos Journal

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