| The transcriptional regulation of glucose homeostasis is a central tenet of biology. In metazoans, this function is performed by the Myc-related transcriptional activators, MondoA and ChREBP. ChREBP operates predominantly in liver and promotes the conversion of high levels of intracellular glucose to lipid for energy storage and membrane synthesis. MondoA operates predominantly in skeletal muscle and promotes the conversion of high levels of intracellular glucose to ATP for immediate use in this highly catabolic tissue type. The experiments presented here detail how MondoA:Mlx heterodimers sense and respond to glucose. The hexokinase-dependent phosphorylation of glucose to G6P stimulates nuclear accumulation and transcriptional activity of MondoA:Mlx, which in turn governs 75% of glucose-dependent transcription. In high glucose conditions, MondoA activates a negative regulator of glucose uptake, thioredoxin interacting protein (TXNIP) to downregulate further glucose uptake. This negative feedback loop is conserved in all cell types tested. MondoA:Mlx shuttles between mitochondria and the nucleus in high and low glucose conditions; G6P and heterodimerization with Mlx promote nuclear accumulation of the heterodimer. The N-terminal Mondo Conserved Regions (MCRs) of MondoA define the glucose-dependent character of the protein. In conjunction with the C-terminal DNA binding domain, the MCRs mediate activation of MondoA:Mlx heterodimers through three distinct steps: nuclear accumulation, promoter occupancy, and coactivator recruitment. Each of these steps is glucose-dependent, and requires the 12-amino acid MCRII domain. In sum, MondoA is essential for intracellular glucose homeostasis, MondoA activity is regulated at multiple glucose-dependent steps, and MondoA-dependent target genes control intracellular glucose availability. |
