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Trypanosoma cruzi senses intracellular heme levels and regulates heme homeostasis by modulating TcHTE protein expression

By Lucas Pagura, Evelyn Tevere, Marcelo L. Merli, Julia A. Cricco

Posted 10 Jan 2020
bioRxiv DOI: 10.1101/2020.01.10.901934

Heme is an essential cofactor for many biological processes in aerobic organisms. Unlike most organisms, which can synthesize it de novo through a conserved pathway, the etiological agent of Chagas disease, Trypanosoma cruzi , as well as other trypanosomatids relevant for human health, are heme auxotrophs; thereby they must import it from the hosts. Tc HTE protein is involved in T. cruzi heme transport, although its specific role remains elusive. In the present work we studied endogenous Tc HTE in the different life cycle stages of the parasite in order to gain insight in its function in heme transport and homeostasis. We have confirmed that Tc HTE is predominantly detected in replicative stages (epimastigote and amastigote). We have also demonstrated that T. cruzi epimastigotes can sense intracellular heme content by an unknown mechanism and regulates heme transport to adapt to changing conditions. Based on these results, we propose a model in which T. cruzi senses intracellular heme and regulates heme transport activity adjusting the expression of Tc HTE. The elucidation and characterization of heme transport and homeostasis will contribute to a better understanding of T. cruzi biology as well as other trypanosomatids, pointing out this pathway as a novel drug target for therapeutics. ### Competing Interest Statement The authors have declared no competing interest. * Tc HTE : T. cruzi Heme Transport Enhancer r Tc HTE.His-GFP : recombinant Tc HTE HRG : Heme-response Gene LHR1 : Leishmania heme response 1 Tb HRG : T. brucei heme-responsive gene TMD : transmembrane domain qRT-PCR : quantitative real-time PCR SnMP : Sn(IV) mesoporphyrin ZnMP : Zn(II) mesoporphyrin LIT : Liver Infusion Tryptose DMEM : Dulbecco’s modified Eagle’s medium FBS : fetal bovine serum DAPI : 4’,6-Diamidino-2-Phenylindole GFP : green fluorescent protein MOI : multiplicity of Infection WT : wild-type

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