LAUSR

Macropinocytosis mediates non-selective bulk uptake of extracellular fluid. It is the major route by which axenic Dictyostelium cells obtain nutrients and has emerged as a nutrient-scavenging pathway for mammalian cells. How environmental and cellular nutrient status modulates macropinocytic activity is not well understood. By developing a high-content imaging-based genetic screen in Dictyostelium, we identified Slc15A, an oligopeptide transporter localized at the plasma membrane and early macropinosome, as a novel macropinocytosis regulator. We show that deletion of slc15A, but not two other related slc15 genes, leads to reduced macropinocytosis, slower cell growth, and aberrantly increased autophagy in cells grown in nutrient-rich medium. Expression of Slc15A or supplying cells with free amino acids rescues these defects. In contrast, expression of transport-defective Slc15A or supplying cells with amino acids in their di-peptide forms fails to rescue these defects. Therefore, Slc15A modulates the level of macropinocytosis by maintaining the intracellular availability of key amino acids via oligopeptide extraction from the early macropinocytic pathway. We propose that Slc15A constitutes part of a positive feedback mechanism coupling cellular nutrient status and macropinocytosis.