title: MondoA-Mlx transcriptional activity is limited by mTOR-MondoA interaction.
abstract: Mammalian target of rapamycin (mTOR) integrates multiple signals, including nutrient status, growth factor availability, and stress, to regulate cellular and organismal growth. How mTOR regulates transcriptional programs in response to these diverse stimuli is poorly understood. MondoA and its obligate transcription partner Mlx are basic helix-loop-helix leucine zipper (bHLHZip) transcription factors that sense and execute a glucose-responsive transcriptional program. MondoA-Mlx complexes activate expression of thioredoxin-interacting protein (TXNIP), which is a potent inhibitor of cellular glucose uptake and aerobic glycolysis. Both mTOR and MondoA are central regulators of glucose metabolism, yet whether they interact physically or functionally is unknown. We show that inhibition of mTOR induces MondoA-dependent expression of TXNIP, coinciding with reduced glucose uptake. Mechanistically, mTOR binds to MondoA in the cytoplasm and prevents MondoA-Mlx complex formation, restricting MondoA's nuclear entry and reducing TXNIP expression. Further, we show that mTOR inhibitors and reactive oxygen species (ROS) regulate interaction between MondoA and mTOR in an opposing manner. Like mTOR's suppression of the MondoA-TXNIP axis, MondoA can also suppress mTOR complex 1 (mTORC1) activity via its direct transcriptional regulation of TXNIP. Collectively, these studies reveal a regulatory relationship between mTOR and the MondoA-TXNIP axis that we propose contributes to glucose homeostasis.
authors.affiliation: Huntsman Cancer Institute, Department of Oncological Sciences, University of Utah, Salt Lake City, Utah, USA mohan.kaadige@hci.utah.edu don.ayer@hci.utah.edu.
authors.forename: Mohan R
authors.initials: MR
authors.lastname: Kaadige
authors.affiliation: Huntsman Cancer Institute, Department of Oncological Sciences, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Jingye
authors.initials: J
authors.lastname: Yang
authors.affiliation: Huntsman Cancer Institute, Department of Oncological Sciences, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Blake R
authors.initials: BR
authors.lastname: Wilde
authors.affiliation: Huntsman Cancer Institute, Department of Oncological Sciences, University of Utah, Salt Lake City, Utah, USA mohan.kaadige@hci.utah.edu don.ayer@hci.utah.edu.
authors.forename: Donald E
authors.initials: DE
authors.lastname: Ayer
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D049109:Cell Proliferation; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D051379:Mice; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D013879:Thioredoxins / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002352:Carrier Proteins; C485496:MLXIP protein, human; C550079:MondoA protein, mouse; D017382:Reactive Oxygen Species; C486715:TXNIP protein, human; C445672:Txnip protein, mouse; D013879:Thioredoxins; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D005947:Glucose