MLX phosphorylation stabilizes the ChREBP-MLX heterotetramer on tandem E-boxes to control carbohydrate and lipid metabolism.

Summary

This mechanistic study demonstrates that phosphorylation of MLX by CK2 and GSK3 is required to assemble and stabilize the ChREBP–MLX heterotetramer on ChoREs, enabling carbohydrate/lipid gene transcription. Elevated glucose-6-phosphate inhibits MLX phosphorylation, dampening ChREBP–MLX activity.

Key Findings

• MLX phosphorylation on a conserved motif is necessary for ChREBP–MLX heterotetramer assembly on ChoREs and for downstream transcriptional activity.
• CK2 and GSK3 are identified as MLX kinases; their action stabilizes the heterotetramer.
• High intracellular glucose-6-phosphate inhibits MLX phosphorylation and impairs ChREBP–MLX function.

Clinical Implications

While preclinical, the CK2/GSK3–MLX phosphorylation axis could be leveraged to fine-tune ChREBP activity in conditions such as nonalcoholic fatty liver disease, hypertriglyceridemia, and type 2 diabetes.

Limitations

• Abstract suggests incomplete physiological validation details; disease-model efficacy and in vivo metabolic outcomes are not described.
• Translational relevance to specific tissues and human pathophysiology requires further work.

Future Directions

Define tissue-specific MLX phosphorylation dynamics in vivo, test pharmacologic modulation of CK2/GSK3–MLX in metabolic disease models, and map genome-wide ChoRE occupancy under altered phosphorylation.