419 Glucose controls protein-protein interactions and epidermal differentiation

Glucose serves as a universal energy currency in living organisms, however, its potential non-energetic biomolecular functions are less well defined. was among the most increased analytes >14,000 assessed across epidermal differentiation, an elevation verified tissue engineered with fluorescent glucose sensors. Free accumulation, but not metabolism, essential for differentiation and required GLUT1, GLUT3, SGLT1 transporters. Consistent this, decreasing cellular levels, by restricting available or increasing intracellular catabolizing enzymes, HK1/2 G6PD, blocked also rescued non-metabolizable analog. Furthermore, RNA-seq analysis of glucose-depleted revealed 34% genes downregulated part gene signature. ATAC-seq identified candidate transcription factors (TFs) that may act on glucose-regulated genes, including ZNF750, NFE2L2, IRF6. affinity chromatography azido-glucose click chemistry direct binding to variety regulatory proteins, IRF6 TF whose knockout confirmed requirement glucose-dependent differentiation. Small molecule docking models suggest binds within DNA domain mediated dimerization, affinity, genomic targeting. The IRF6R84C mutant found poorly differentiated cancers ectodermal dysplasias unable bind glucose. These data demonstrate role modulating protein multimerization control