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Small molecule regulation of cell function is an understudied area of trypanosomatid biology. In  Trypanosoma brucei  diacylglycerol (DAG) stimulates endocytosis of transferrin (Tf). However, it is not known whether other trypanosomatidae respond similarly to the lipid. Further, the biochemical pathways involved in DAG signaling to the endocytic system in  T. brucei  are unknown, as the parasite genome does not encode canonical DAG receptors ( e.g.  C1-domains). We established that DAG stimulates endocytosis of Tf in  Leishmania major , and we evaluated possible effector enzymes in the pathway with multiple approaches. First, a heterologously expressed glycosylphosphatidylinositol phospholipase C ( GPI-PLC ) activated endocytosis of Tf 300% in  L. major . Second, exogenous phorbol ester and DAGs promoted Tf endocytosis in  L. major . In search of possible effectors of DAG signaling, we discovered a novel C1-like domain ( i.e.  C1_5) in trypanosomatids, and we identified protein Tyr kinases (PTKs) linked with C1_5 domains in  T. brucei ,  T. cruzi , and  L. major . Consequently, we hypothesized that trypanosome PTKs might be effector enzymes for DAG signaling. General uptake of Tf was reduced by inhibitors of either Ser/Thr or Tyr kinases. However, DAG-stimulated endocytosis of Tf was blocked only by an inhibitor of PTKs, in both  T. brucei  and  L. major . We conclude that (i) DAG activates Tf endocytosis in  L. major , and that (ii) PTKs are effectors of DAG-stimulated endocytosis of Tf in trypanosomatids. DAG-stimulated endocytosis of Tf may be a  T. brucei  adaptation to compete effectively with host cells for vertebrate Tf in blood, since DAG does not enhance endocytosis of Tf in human cells.

Diacylglycerol-Stimulated Endocytosis of Transferrin in Trypanosomatids Is Dependent on Tyrosine Kinase Activity