Control of XPR1-dependent cellular phosphate efflux by InsP 8 is an exemplar for functionally-exclusive inositol pyrophosphate signaling

Significance Biological roles of inorganic phosphate require careful regulation of its transport across cell membranes, but mechanisms are poorly understood. We demonstrate that a major cellular phosphate export protein, XPR1, is regulated by the most “energetic” of cell signaling molecules—1,5-bisdiphosphoinositol 1,2,3,4-tetrakisphosphate (InsP8 ). We derive this conclusion by showing reduced XPR1-mediated phosphate efflux when InsP8 synthesis was attenuated by genetic or pharmacological techniques; phosphate efflux was rescued by using liposomes to deliver into cells metabolically resistant InsP8 analogues. Genetic elimination of InsP8 from an osteosarcoma cell line perturbed phosphate homeostasis and accelerated differentiation into a biomineralization phenotype. We propose that mutations in gene products that regulate InsP8 synthesis might compromiseXPR1 function, with pathological consequences for bone maintenance and ectopic calcification.