A phosphate-sensing organelle regulates phosphate and tissue homeostasis

Abstract

Inorganic phosphate (P_i) is one of the essential molecules for life. However, little is known about intracellular P_i metabolism and signalling in animal tissues¹. Following the observation that chronic P_i starvation causes hyperproliferation in the digestive epithelium of Drosophila melanogaster, we determined that P_i starvation triggers the downregulation of the P_i transporter PXo. In line with P_i starvation, PXo deficiency caused midgut hyperproliferation. Interestingly, immunostaining and ultrastructural analyses showed that PXo specifically marks non-canonical multilamellar organelles (PXo bodies). Further, by P_i imaging with a Förster resonance energy transfer (FRET)-based P_i sensor², we found that PXo restricts cytosolic P_i levels. PXo bodies require PXo for biogenesis and undergo degradation following P_i starvation. Proteomic and lipidomic characterization of PXo bodies unveiled their distinct feature as an intracellular P_i reserve. Therefore, P_i starvation triggers PXo downregulation and PXo body degradation as a compensatory mechanism to increase cytosolic P_i. Finally, we identified connector of kinase to AP-1 (Cka), a component of the STRIPAK complex and JNK signalling³, as the mediator of PXo knockdown- or P_i starvation-induced hyperproliferation. Altogether, our study uncovers PXo bodies as a critical regulator of cytosolic P_i levels and identifies a P_i-dependent PXo-Cka-JNK signalling cascade controlling tissue homeostasis.