A Membrane-bound eIF2 Alpha Kinase Located in Endosomes Is Regulated by Heme and Controls Differentiation and ROS Levels in

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Trypanosoma cruzi proliferates as epimastigotes in the midgut of the insect vector filled with blood meal. There, it accumulates nutrients in specific endosomal organelles. The parasite moves towards the hindgut and when the blood is completely digested, these organelles are consumed. At this moment, the insect is ready for a new feeding cycle that promotes the release of infective metacyclic-trypomastigote forms. We have previously found that such differentiation involves protein synthesis arrest through the phosphorylation of the eukaryotic translation initiation factor 2α (eIF2α). Now, we show that one of the kinases (TCK2) that phosphorylate eIF2α is localized in these endosomes. TcK2 binds and is specifically inhibited by heme derived from blood hemoglobin. We also found that heme inhibits differentiation, suggesting that it is an important signal for differentiation. By generating knockouts of TcK2, we observed an increased accumulation of heme in the cytosol, which induced cellular damage by affecting the reactive oxygen metabolism in the parasite. We conclude that this eIF2α kinase senses cytosolic heme obtained from the blood meal, promoting its storage in the cytosolic organelles. When heme levels are decreased in the cytosol, TcK2 activation can then arrest protein synthesis that is followed by the induction of the differentiation of proliferative epimastigote forms to infective metacyclic-trypomastigotes.

Vyšlo v časopise: A Membrane-bound eIF2 Alpha Kinase Located in Endosomes Is Regulated by Heme and Controls Differentiation and ROS Levels in. PLoS Pathog 11(2): e32767. doi:10.1371/journal.ppat.1004618
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004618

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