Homeostatic coordination of cellular phosphate uptake and efflux requires an organelle-based receptor for the inositol pyrophosphate IP8
Xingyao Li,
Regan B. Kirkpatrick,
Xiaodong Wang,
Charles J. Tucker,
Anuj Shukla,
Henning J. Jessen,
Huanchen Wang,
Stephen B. Shears,
Chunfang Gu
Affiliations
Xingyao Li
Inositol Signaling Group, Signal Transduction Laboratory, National Institute of Environmental, Health Sciences, Research Triangle Park, NC 27709, USA
Regan B. Kirkpatrick
Inositol Signaling Group, Signal Transduction Laboratory, National Institute of Environmental, Health Sciences, Research Triangle Park, NC 27709, USA
Xiaodong Wang
Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Charles J. Tucker
Fluorescence Microscopy and Imaging Center, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA
Anuj Shukla
Institute of Organic Chemistry, and CIBSS - the Center for Integrative Biological Signaling Studies, University of Freiburg, 79104 Freiburg, Germany
Henning J. Jessen
Institute of Organic Chemistry, and CIBSS - the Center for Integrative Biological Signaling Studies, University of Freiburg, 79104 Freiburg, Germany
Huanchen Wang
Inositol Signaling Group, Signal Transduction Laboratory, National Institute of Environmental, Health Sciences, Research Triangle Park, NC 27709, USA; Nucleolar Integrity Group, Signal Transduction Laboratory, National Institute of Environmental, Health Sciences, Research Triangle Park, NC 27709, USA
Stephen B. Shears
Inositol Signaling Group, Signal Transduction Laboratory, National Institute of Environmental, Health Sciences, Research Triangle Park, NC 27709, USA
Chunfang Gu
Inositol Signaling Group, Signal Transduction Laboratory, National Institute of Environmental, Health Sciences, Research Triangle Park, NC 27709, USA; Synaptic & Developmental Plasticity Group, Neurobiology Laboratory, National Institute of Environmental, Health Sciences, Research Triangle Park, NC 27709, USA; Corresponding author
Summary: Phosphate (Pi) serves countless metabolic pathways and is involved in macromolecule synthesis, energy storage, cellular signaling, and bone maintenance. Herein, we describe the coordination of Pi uptake and efflux pathways to maintain mammalian cell Pi homeostasis. We discover that XPR1, the presumed Pi efflux transporter, separately supervises rates of Pi uptake. This direct, regulatory interplay arises from XPR1 being a binding partner for the Pi uptake transporter PiT1, involving a predicted transmembrane helix/extramembrane loop in XPR1, and its hitherto unknown localization in a subset of intracellular LAMP1-positive puncta (named “XLPVs”). A pharmacological mimic of Pi homeostatic challenge is sensed by the inositol pyrophosphate IP8, which functionalizes XPR1 to respond in a temporally hierarchal manner, initially adjusting the rate of Pi efflux, followed subsequently by independent modulation of PiT1 turnover to reset the rate of Pi uptake. These observations generate a unifying model of mammalian cellular Pi homeostasis, expanding opportunities for therapeutic intervention.
