Role of autophagy in stress and drug-responsive cell death in Entamoeba histolytica and its cross-talk with apoptosis-inducing factor

Cell death in unicellular protozoan parasite Entamoeba histolytica is not yet reported though it displays several features of autophagic cell death. Autophagic cell death was reported to take place in ancient protozoans under several stresses. Here we report the occurrence of autophagic cell death in the Entamoeba histolytica trophozoites under oxidative stress as well as by the treatment with metronidazole, the most-widely-used drug for amoebiasis treatment and was shown to generate oxidative stress in the trophozoites. The autophagic flux increases during nutrient deprivation and metronidazole treatment and decreases upon oxidative stress. During oxidative stress the autophagy leads to nucleophagy that is ultimately destined to be digested within the lysosomal chamber. The formation of nucleophagosome depends on the apoptosis-inducing factor (AIF) that translocates to the nucleus from cytoplasm upon oxidative stress. It was experimentally proved that ATG8 (Autophagy-related protein 8) binds with the AIF in the nucleus of the trophozoites and helps in ATG8 recruitment and autophagy initiation overall suggesting that oxidative stress-driven AIF translocation to nucleus results in binding with ATG8 and initiates nucleophagy leading to cell death.