Endocytosis, signal transduction and proteolytic cleaving of human holotransferrin in Entamoeba histolytica

• Published in: International journal for parasitology 2020-10, Vol.50 (12), p.959-967
• Main Authors: Reyes-López, Magda, Piña-Vázquez, Carolina, Pérez-Salazar, Eduardo, de la Garza, Mireya
• Format: Article
• Language: English
• Subjects: Carbohydrate metabolism; Entamoeba histolytica; Signal transduction; Transferrin
• ISSN: 0020-7519; 1879-0135
• DOI: 10.1016/j.ijpara.2020.05.013

[Display omitted] •Human holotransferrin (holoTf) is an iron-containing protein used by Entamoeba histolytica as an iron source.•Entamoeba histolytica transferrin receptor (EhTfR) triggers the signal for parasite proliferation.•HoloTf is endocytosed in clathrin-coated vesicles and travels via the endosomal-lysosomal system.•Signal transduction goes to MAPK and FAK signalling pathways, involving the activation of other PI-3Ks.•Proteins that respond to proliferation signals by holoTf are related to carbohydrate metabolism and cellular protection. Amoebiasis is a parasitic infection of the human large intestine caused by Entamoeba histolytica; this disease mainly affects people from developing countries. To survive, this primitive protozoan has a high demand for iron, and it uses host iron proteins upon invasion. Transferrin (Tf) is a plasma iron-binding protein that transports and delivers iron to all cells. Iron-loaded Tf (holoTf) in humans can support the proliferation of amoebae in vitro by binding to an amoebic TfR (EhTfR), and amoebae endocytose it inside clathrin-coated vesicles. In this study, it was found that EhTfR phosphorylation is required for human holoTf endocytosis by E. histolytica. Once this complex is endocytosed, human holoTf could be degraded with a nutritional purpose by cysteine proteases. HoloTf endocytosis initiates the activation of the mitogen-activated protein kinases (MAPKs) and focal adhesion kinase (FAK) pathways, which induce cell proliferation with phosphoinositide 3-kinase (PI-3 K) and Ca2+ involvement. In the first minutes after holoTf is endocytosed, several proteins are phosphorylated including transketolase, enolase, L-myo-inositol-1-phosphate synthase and phosphoglucomutase, which control carbohydrate metabolism, and heat shock protein-70. The study of these proteins and their signal transduction pathways could be useful for developing future therapies.