MLX phosphorylation is an evolutionarily conserved mechanism to promote lipid storage and sugar tolerance

To cope with food scarcity, animals store energy as lipids, which are produced from carbohydrates via de novo lipogenesis (DNL). The carbohydrate-responsive ChREBP-MLX complex is a master transcriptional regulator for DNL and lipid storage. However, our understanding of molecular mechanisms, particularly signaling pathways, controlling ChREBP-MLX complex remains incomplete. Here, we show that mammalian MLX is phosphorylated on an evolutionarily conserved motif and that MLX phosphorylation is necessary for ChREBP-MLX transcriptional activity. In Drosophila, MLX phosphorylation is essential for lipid storage and sugar tolerance during fly development. Furthermore, we identified CK2 as an MLX kinase. Although glucose phosphorylation is required for ChREBP-MLX activity, accumulation of glucose-6-phosphate (G6P) inhibits CK2-mediated MLX phosphorylation and thereby ChREBP-MLX activity. We propose that the evolutionarily conserved MLX phosphorylation is a rheostat that adjusts ChREBP-MLX activity in response to the carbohydrate availability ultimately controlling energy homeostasis.