Abstract
The TOR (Target of Rapamycin) pathway is a highly-conserved signaling pathway in eukaryotes that regulates cellular growth and stress responses. The cellular response to amino acids or carbon sources such as glucose requires anchoring of the TOR kinase complex to the lysosomal/vacuolar membrane by the Ragulator (mammals) or EGO (yeast) protein complex. Here we report a connection between the TOR pathway and circadian (daily) rhythmicity. The molecular mechanism of circadian rhythmicity in all eukaryotes has long been thought to be transcription/translation feedback loops (TTFLs). In the model eukaryote Neurospora crassa, a TTFL including FRQ (frequency) and WCC (white collar complex) has been intensively studied. However, it is also well-known that rhythmicity can be seen in the absence of TTFL functioning. We previously isolated uv90 as a mutation that compromises FRQ-less rhythms and also damps the circadian oscillator when FRQ is present. We have now mapped the uv90 gene and identified it as NCU05950, homologous to the TOR pathway proteins EGO1 (yeast) and LAMTOR1 (mammals), and we have named the N. crassa protein VTA (vacuolar TOR-associated protein). The protein is anchored to the outer vacuolar membrane and deletion of putative acylation sites destroys this localization as well as the protein’s function in rhythmicity. A deletion of VTA is compromised in its growth responses to amino acids and glucose. We conclude that a key protein in the complex that anchors TOR to the vacuole plays a role in maintaining circadian (daily) rhythmicity. Our results establish a connection between the TOR pathway and circadian rhythms and point towards a network integrating metabolism and the circadian system.
Highlights
The TOR (Target of Rapamycin) pathway is a highly conserved cellular pathway in eukaryotes that monitors nutritional and stress signals from both extracellular and intracellular sources to regulate cellular growth, division, autophagy and stress responses
Using the fungus Neurospora crassa as a model organism, we have discovered a gene that is important for maintaining rhythms that continue without the known feedback loop
We have found that this gene codes for a protein that was already known to be important in helping cells to adjust their growth rate to adapt to varying availability of nutrients
Summary
The TOR (Target of Rapamycin) pathway is a highly conserved cellular pathway in eukaryotes that monitors nutritional and stress signals from both extracellular and intracellular sources to regulate cellular growth, division, autophagy and stress responses It has been extensively studied in mammals [1] and yeast [2]. There is evidence that other pathways related to amino acid availability intersect with TORC1 signaling, including the GAAC (general amino acid control) pathway, which upregulates amino acid transport and metabolism in response to amino acid starvation, and the SPS (Ssy1-Ptr3-Ssy5) pathway that upregulates amino acid transport in response to extracellular amino acids [3] In both yeast and mammals, localization of the TOR complex to the lysosomal/vacuolar membrane is essential for its activation [4]. Disruptions in the TOR pathway have been associated with human pathologies such as metabolic disease, cancer, and age-related diseases [7, 8]
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