%0 Journal Article %T Nutrient-regulated control of lysosome function by signaling lipid conversion. %A Ebner M %A Puchkov D %A López-Ortega O %A Muthukottiappan P %A Su Y %A Schmied C %A Zillmann S %A Nikonenko I %A Koddebusch J %A Dornan GL %A Lucht MT %A Koka V %A Jang W %A Koch PA %A Wallroth A %A Lehmann M %A Brügger B %A Pende M %A Winter D %A Haucke V %J Cell %V 186 %N 24 %D 2023 11 22 %M 37883971 %F 66.85 %R 10.1016/j.cell.2023.09.027 %X Lysosomes serve dual antagonistic functions in cells by mediating anabolic growth signaling and the catabolic turnover of macromolecules. How these janus-faced activities are regulated in response to cellular nutrient status is poorly understood. We show here that lysosome morphology and function are reversibly controlled by a nutrient-regulated signaling lipid switch that triggers the conversion between peripheral motile mTOR complex 1 (mTORC1) signaling-active and static mTORC1-inactive degradative lysosomes clustered at the cell center. Starvation-triggered relocalization of phosphatidylinositol 4-phosphate (PI(4)P)-metabolizing enzymes reshapes the lysosomal surface proteome to facilitate lysosomal proteolysis and to repress mTORC1 signaling. Concomitantly, lysosomal phosphatidylinositol 3-phosphate (PI(3)P), which marks motile signaling-active lysosomes in the cell periphery, is erased. Interference with this PI(3)P/PI(4)P lipid switch module impairs the adaptive response of cells to altering nutrient supply. Our data unravel a key function for lysosomal phosphoinositide metabolism in rewiring organellar membrane dynamics in response to cellular nutrient status.