Macropinocytosis is the process by which cells internalise large volumes of fluid into plasma membrane-derived vesicles, and it has been suggested as a mechanism for nutrient uptake. In macrophages, macropinocytosis can be initiated by the growth factor colony stimulating factor 1 (CSF1), among other stimuli. The molecular mechanisms involved in macropinocytosis have been extensively studied; however, the regulation of this process is still unclear. Now, Joel Swanson and colleagues (Mendel et al., 2022) hypothesise that extracellular nutrients are involved. By measuring the uptake of a specific fluorescent marker for macropinocytosis, the authors examine the effect of single amino acids and reveal that nine amino acids suppress this process. Moreover, suppression of macropinocytosis in macrophages stimulated with CSF1 or interleukin 34 suggests that these amino acids selectively suppress CSF1 receptor (CSF1R)-dependent macropinocytosis by promoting loss of CSF1R. Interestingly, incubation with the suppressive amino acid leucine reduces the size of macropinosomes that form in response to CSF1. Taken together, these results uncover a new mechanism whereby essential amino acids downregulate macropinocytosis in a CSF1R-dependent manner, which could have implications for the regulation of macrophage growth and function.
