Authors: Carla E. Cadena del Castillo, Onur Deniz, Femke van Geest, Lore Rosseels, Ingrid Stockmans, Marius Robciuc, Sebastien Carpentier, Bettina K. Wölnerhanssen, Anne Christin Meyer-Gerspach, Ralph Peterli, Ville Hietakangas, Mitsugu Shimobayashi
Published: 2025-03-12
Source: Full article
Carbohydrate-responsive element binding protein (ChREBP) and Max-like protein X (MLX) form a heterodimeric transcription factor complex that couples intracellular sugar levels to carbohydrate and lipid metabolism. To promote the expression of target genes, two ChREBP-MLX heterodimers form a heterotetramer to bind a tandem element with two adjacent E-boxes, called carbohydrate-responsive element (ChoRE). How the ChREBP-MLX hetero-tetramerization is achieved and regulated remains poorly understood. Here, we show that MLX phosphorylation on an evolutionarily conserved motif is necessary for the heterotetramer formation on the ChoRE and the transcriptional activity of the ChREBP-MLX complex. We identified casein kinase 2 (CK2) and glycogen synthase kinase 3 (GSK3) as MLX kinases. High intracellular glucose-6-phosphate accumulation inhibits MLX phosphorylation and heterotetramer formation on the ChoRE, impairing ChREBP-MLX activity. Physiologically, MLX phosphorylation is necessary in