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

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. Overall design: A total of six samples were analyzed. Three samples were independent wild-type replicates and three were ccr4D mutant replicates