InteractiveFly: GeneBrief
Repressed by TOR: Biological Overview | References
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Gene name - Repressed by TOR
Synonyms - Cytological map position - 96A7-96A9 Function - transcription factor Keywords - together with its binding partner encoded by REPTOR-BP, mediates much of the transcriptional response observed upon Tor complex 1 inhibition - plays critical roles in maintaining energy homeostasis and promoting animal survival upon nutrient restriction |
Symbol - REPTOR
FlyBase ID: FBgn0039209 Genetic map position - chr3R:24,557,368-24,582,864 Classification - Basic leucine zipper (bZIP) domain Cellular location - nuclear and cytoplasmic |
| Recent literature | Saavedra, P., Dumesic, P. A., Hu, Y., Filine, E., Jouandin, P., Binari, R., Wilensky, S. E., Rodiger, J., Wang, H., Chen, W., Liu, Y., Spiegelman, B. M. and Perrimon, N. (2023). REPTOR and CREBRF encode key regulators of muscle energy metabolism. Nat Commun 14(1): 4943. PubMed ID: 37582831
Summary: Metabolic flexibility of muscle tissue describes the adaptive capacity to use different energy substrates according to their availability. The disruption of this ability associates with metabolic disease. Using a Drosophila model of systemic metabolic dysfunction triggered by yorkie-induced gut tumors, this study showed that the transcription factor REPTOR is an important regulator of energy metabolism in muscles. Evidence is presented that REPTOR is activated in muscles of adult flies with gut yorkie-tumors, where it modulates glucose metabolism. Further, in vivo studies indicate that sustained activity of REPTOR is sufficient in wildtype muscles to repress glycolysis and increase tricarboxylic acid (TCA) cycle metabolites. Consistent with the fly studies, higher levels of CREBRF, the mammalian ortholog of REPTOR, reduce glycolysis in mouse myotubes while promoting oxidative metabolism. Altogether, these results define a conserved function for REPTOR and CREBRF as key regulators of muscle energy metabolism. |
TORC1, in Drosophila consisting of Target of rapamycin, Raptor and Lst8) regulates growth and metabolism, in part, by influencing transcriptional programs. This study has identified REPTOR and REPTOR-BP, both leucine zipper DNA-binding proteins, as transcription factors downstream of TORC1 that are required for approximately 90% of the transcriptional induction that occurs upon TORC1 inhibition in Drosophila. Thus, REPTOR and REPTOR-BP are major effectors of the transcriptional stress response induced upon TORC1 inhibition, analogous to the role of FOXO downstream of Akt. When TORC1 is active, it phosphorylates REPTOR on Ser527 and Ser530, leading to REPTOR cytoplasmic retention. Upon TORC1 inhibition, REPTOR becomes dephosphorylated in a PP2A-dependent manner, shuttles into the nucleus, joins its partner REPTOR-BP to bind target genes, and activates their transcription. In vivo functional analysis using knockout flies reveals that REPTOR and REPTOR-BP play critical roles in maintaining energy homeostasis and promoting animal survival upon nutrient restriction (Tiebe, 2015).
Target of rapamycin complex 1 (TORC1) integrates information on energy and nutrient status in eukaryotic cells. Under high-nutrient and -energy conditions, TORC1 drives translation, ribosome biogenesis, mitochondrial activity, lipid synthesis, nucleotide synthesis, and glycolysis. TORC1, thereby, couples activity of cellular anabolic and catabolic pathways to nutrient and energy supply. TORC1 is frequently mis-regulated in diseases such as cancer, diabetes, obesity, and neurodegeneration (Tiebe, 2015).
TORC1 regulates growth and metabolism by phosphorylating target proteins, such as S6K and 4E-BP, involved in translational regulation. Phosphorylation of targets changes very rapidly upon altered TORC1 activity, allowing cells to adapt quickly to changing environmental conditions. In addition, TORC1 also has long-lasting impact on cellular behavior through the control of transcriptional programs. This occurs by directly or indirectly modulating the activity of transcription factors such as SREBP, HIF1a, PGC-1a, TIF1a, PPARa, Atf4 (CREB2), TFEB, and TFE3 (Tiebe, 2015).
The TORC1 signaling pathway is highly conserved through evolution, thereby enabling the use of model organisms such as Drosophila for discovery of novel pathway components. Recent studies in Drosophila analyzed the impact of TORC1 signaling on cellular transcription. In Drosophila S2 cells, inhibition of TORC1 with rapamycin leads to numerous transcriptional changes. Genes involved in anabolic processes such as ribosome biogenesis are strongly repressed upon TORC1 inhibition. Previous work showed that this occurs via downregulation of myc activity (Teleman, 2008). A second class of genes is activated upon TORC1 inhibition. Although the function of these genes is less understood, they probably represent the genes needed for cells to adapt to conditions yielding reduced TORC1 activity, such as low nutrient availability. This study aimed to find the transcription factor responsible for mediating this upregulation upon TORC1 inhibition. The discovery is reported of these factors, which, surprisingly, are required for mediating most of the transcriptional induction that takes place upon TORC1 inhibition and play important roles in maintaining energy homeostasis in vivo (Tiebe, 2015).
This study has identify two uncharacterized genes, CG13624 and CG18619, which are termed REPTOR and REPTOR-BP, res