| MLX, a basic helix-loop-helix leucine zipper transcription factor in the Myc/Max/Mad superfamily, heterodimerizes obligatorily with tissue-specific partners MLXIP (MondoA) or MLXIPL (ChREBP) to sense glucose metabolites and regulate metabolic gene expression. Both complexes feature bHLHZip domains for E-box (CACGTG) DNA binding and N-terminal activation domains responsive to glucose-6-phosphate via hexokinase-catalyzed phosphorylation, with cytoplasmic-mitochondrial retention in low glucose shifting to nuclear accumulation upon metabolite elevation. MLX/MLXIP heterodimers translocate rapidly to the nucleus following 2-deoxyglucose exposure, binding ChoRE promoters of thioredoxin-interacting protein (TXNIP), ARRDC4, and glycolytic enzymes like HK2, PFKFB3, LDH-A to drive >75% of glucose-induced transcription, while promoting histone H4 acetylation for open chromatin. MLX/MLXIPL similarly activates lipogenic targets in the liver, with MLX phosphorylation stabilizing heterotetramers on DNA for sustained activity. Glucose sensing integrates hexokinase activity, as inhibitors like 3-bromopyruvate block nuclear import, and MondoA mutations disrupting MLX dimerization abolish response. MLX orchestrates glucose homeostasis by inducing glycolysis/lipogenesis genes and repressing uptake via TXNIP, balancing nutrient flux in muscle, liver, and proliferating cells. MLX-null impairs myokine secretion, including IGF2 for myoblast fusion/Akt activation, blunts muscle regeneration, and disrupts sugar tolerance/lipid balance. Dysregulation contributes to diabetes through failed TXNIP induction and cancer via Myc cooperation, reprogramming metabolism. |
