MondoA senses adenine nucleotides: transcriptional induction of thioredoxin-interacting protein

The MondoA:Mlx transcription complex plays a pivotal role in glucose homeostasis by activating target gene expression in response to glucose-6-phosphate (G6P), the first reaction intermediate in glycolysis. Thioredoxin-interacting protein (TXNIP) is a direct and glucose-responsive target of MondoA that triggers a negative feedback loop by restricting glucose uptake when G6P levels increase. We show here that TXNIP expression is also activated by 5-aminoimidazole-4-carboxamide ribofuranoside (AICAR) and adenosine. Using pharmacologic inhibitors and genetic knockdowns of purine metabolic enzymes, we establish that TXNIP induction by AICAR and adenosine requires their cellular uptake and metabolism to adenine nucleotides. AICAR induction of TXNIP depended on MondoA but was independent of AMPK activation and calcium. Our findings have two important implications. First, in addition to activating AMPK, AICAR may have AMPK-independent effects on gene expression by regulating MondoA:Mlx activity following its flux into the adenine nucleotide pool. Second, MondoA:Mlx complexes sense elevated levels of G6P and adenine nucleotides to trigger a TXNIP-dependent feedback inhibition of glycolysis. We propose that this mechanism serves as checkpoint to restore metabolic homeostasis.
Source: BJ Gene - Category: Biochemistry Authors: Tags: BJ Metabolism Source Type: research