Glucose-dependent transcriptional activity of the mondoa:MLX heterodimer
Creators: name: Peterson, Christopher William
Publisher: name: University of Utah
Year: 2012
Subjects: ARRDC4
ChREBP
Glucose metabolism
Mitochondria
MondoA
TXNIP

description: 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 Nterminal  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 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 Nterminal  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 theseThe 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 Nterminal  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.