Caffeine Impairs Phagocytosis and Pinocytosis in Dictyostelium by Modulating mTORC2 Activity

Nutrient uptake via phagocytosis and pinocytosis is essential for the survival and growth of Dictyostelium discoideum, with the mTOR signaling pathway, comprising mTORC1 and mTORC2 complexes, playing a pivotal regulatory role. This study investigated how caffeine and adenosine influence these processes in wild-type (KAX3) and mTORC2-deficient (lst8- and rip3-) cells. Caffeine enhanced phagocytosis rates while inhibiting fluid-phase pinocytosis in KAX3 cells, implicating mTORC2 as a target. Similarly, lst8- and rip3- mutants exhibited increased phagocytosis, confirming that mTORC2 suppresses this process under normal conditions. Fluid uptake in rip3- mutants was less inhibited than in lst8- mutants, suggesting mTORC1’s involvement in pinocytosis regulation alongside upstream proteins. The caffeine resistance observed in lst8- and rip3- mutants reinforced the specificity of mTORC2 as a caffeine target. Adenosine, known for its growth-promoting effects, had no significant impact on phagocytosis or pinocytosis, indicating its action is independent of nutrient uptake. These findings suggest that while mTORC2 plays a central role in suppressing phagocytosis, pinocytosis involves a more complex interplay between mTORC1, mTORC2, and other regulators.