Commentary: Cellular functions of vitamin D-binding protein

Abstract

The classical roles of plasma vitamin D-binding protein (DBP) are the transport of vitamin D and its metabolites in blood, as well as because of its actin-binding affinity, the removal of any actin that escapes into the circulation when cells are damaged or destroyed. It is also apparent that DBP has functions related to the activity of lymphoid cells that are independent of its role as a vehicle for delivering vitamin D metabolites around the body. A separate major function of DBP was revealed with the discovery of the endocytic activity of cell membrane proteins megalin and cubilin, in internalizing DBP into cells in a number of different organs, particularly the kidney and skeletal muscle. Within a cell, DBP binds specifically to cytoplasmic actin filaments. Because most DBP in plasma is in the apo-configuration, that which binds to actin within specific cells, provides an array of empty binding sites that enable free 25-hydroxyvitamin D (25(OH)D), that diffuses into those cells, to be retained on the DBP-actin structure. The retention of 25(OH)D diffusing into renal proximal tubule cells provides the substrate, after DBP proteolysis, for the 1-hydroxylase which generates the vitamin D hormone, 1,25-dihydroxyvitamin D (1,25(OH)₂D). In skeletal muscle cells, the 25(OH)D that accumulates on the internalized DBP-actin complex, diffuses back to the circulation when that DBP undergoes proteolysis. This diffusion of 25(OH)D into and out of skeletal muscle cells, mediated by the internalized apo-DBP mechanism, accounts for the long half-life of 25(OH)D in the circulation and the role this process plays in maintaining vitamin D status.