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bioRxiv
BIORXIV
bioRxiv
2692-8205
Cold Spring Harbor Laboratory

10.1101/2024.09.04.611172
preprint
2
Article
MLX phosphorylation stabilizes the ChREBP-MLX heterotetramer on tandem E-boxes to control carbohydrate and lipid metabolism
Cadena del Castillo Carla E
Deniz Onur
van Geest Femke
Rosseels Lore
Stockmans Ingrid
Robciuc Marius
Carpentier Sebastien
Wölnerhanssen Bettina K.
Meyer-Gerspach Anne Christin
Peterli Ralph
Hietakangas Ville
Shimobayashi Mitsugu
05 9 2024
2024.09.04.611172https://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
http://biorxiv.org/lookup/doi/10.1101/2024.09.04.611172
nihpp-2024.09.04.611172.pdf
Abstract

The heterodimeric ChREBP-MLX transcription factor complex is a key mediator 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 CK2 and GSK3 as MLX kinases that coordinately phosphorylate MLX. 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 Drosophila to maintain sugar tolerance and lipid homeostasis. Our findings suggest that MLX phosphorylation is a key mechanism for the ChREBP-MLX heterotetramer formation to regulate carbohydrate and lipid metabolism.
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