Figure 5.

Graphical representation of the suggested interplay between vitamin D and legumain. Left panel: Vitamin D (VD₃) promotes legumain expression and activity through transcriptional upregulation of the legumain gene (LGMN). The free fraction of circulating VD₃ metabolites diffuse through plasma membranes. 25-hydroxyvitamin D (25(OH)D₃) is hydroxylated by 1α-hydroxylase (CYP27B1), forming the active metabolite 1α,25-dihydroxyvitamin D (1,25(OH)₂D₃). 1,25(OH)₂D₃ binds to the nuclear vitamin D receptor (VDR) and promotes transcription of legumain (LGMN). Synthesized prolegumain is either sorted and activated in the endolysosomal system or released to the extracellular environment. Right panel: In the proximal tubular epithelium, 25(OH)D₃ bound to vitamin D binding protein (VDBP) is internalized from the tubular lumen through a megalin/cubilin-mediated process. The vitamin D metabolite is released, enabling subsequent hydroxylation by 1α-hydroxylase (CYP27B1) or 24-hydroxylase (CYP24A1), and VDBP is cleaved by legumain in the endolysosomal system. VDBP cleavage by legumain might be important in controlling the systemic level of vitamin D metabolites. Created with BioRender.com (accessed on 11 December 2023).