title: Glutamine-dependent anapleurosis dictates glucose uptake and cell growth by regulating MondoA transcriptional activity.
abstract: Glucose and glutamine are abundant nutrients required for cell growth, yet how cells sense and adapt to changes in their levels is not well understood. The MondoA transcription factor forms a heterocomplex with its obligate partner Mlx to regulate approximately 75% of glucose-dependent transcription. By mediating glucose-induced activation of thioredoxin-interacting protein (TXNIP), MondoA:Mlx complexes directly repress glucose uptake. We show here that glutamine inhibits transcriptional activation of TXNIP by triggering the recruitment of a histone deacetylase-dependent corepressor to the amino terminus of MondoA. Therefore, in the presence of both glucose and glutamine, TXNIP expression is low, which favors glucose uptake and aerobic glycolysis; the Warburg effect. Consistent with MondoA functioning upstream of TXNIP, MondoA knockdown reduces TXNIP expression, elevates glucose uptake and stimulates cell proliferation. Although glutamine has many intracellular fates, a cell permeable analog of a tricarboxylic acid cycle (TCA) intermediate, alpha-ketoglutarate, also blocks the transcriptional activity of MondoA at the TXNIP promoter and stimulates glucose uptake. Together our data suggest that glutamine-dependent mitochondrial anapleurosis dictates glucose uptake and aerobic glycolysis by blocking MondoA:Mlx-dependent transcriptional activation of TXNIP. We propose that this previously unappreciated coordination between glutamine and glucose utilization defines a metabolic checkpoint that restricts cell growth when subthreshold levels of these essential nutrients are available.
authors.affiliation: Huntsman Cancer Institute, Department of Oncological Sciences, University of Utah, 2000 Circle of Hope, Room 4365, Salt Lake City, UT 84112-5550, USA.
authors.forename: Mohan R
authors.initials: MR
authors.lastname: Kaadige
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Looper
authors.forename: Sadhaasivam
authors.initials: S
authors.lastname: Kamalanaadhan
authors.forename: Donald E
authors.initials: DE
authors.lastname: Ayer
mesh_terms: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D002952:Citric Acid Cycle; D005947:Glucose / Q000378:metabolism*; D005973:Glutamine / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002352:Carrier Proteins; C485496:MLXIP protein, human; C486715:TXNIP protein, human; D005973:Glutamine; D005947:Glucose
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