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 (InsP 8 ). We derive this conclusion by showing reduced XPR1-mediated phosphate efflux when InsP 8 synthesis was attenuated by genetic or pharmacological techniques; phosphate efflux was rescued by using liposomes to deliver into cells metabolically resistant InsP 8 analogues. Genetic elimination of InsP 8 from an osteosarcoma cell line perturbed phosphate homeostasis and accelerated differentiation into a biomineralization phenotype. We propose that mutations in gene products that regulate InsP 8 synthesis might compromise XPR1 function, with pathological consequences for bone maintenance and ectopic calcification.