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dc.contributor.authorCabello-Donayre, M.es_ES
dc.contributor.authorMalagarie-Cazenave, Sophiees_ES
dc.contributor.authorCampos-Salinas, Jennyes_ES
dc.contributor.authorGálvez, Francisco J.es_ES
dc.contributor.authorRodriguez-Martinez, Albaes_ES
dc.contributor.authorPineda-Molina, Estelaes_ES
dc.contributor.authorOrrego, Lina M.es_ES
dc.contributor.authorMartínez-García, Martaes_ES
dc.contributor.authorSánchez-Cañete, María P.es_ES
dc.contributor.authorEstévez, Antonio M.es_ES
dc.contributor.authorPérez-Victoria, J. M.es_ES
dc.identifier.citationMolecular Microbiologyes_ES
dc.description.abstractPathogenic trypanosomatid parasites are auxotrophic for heme and they must scavenge it from their human host. Trypanosoma brucei (responsible for sleeping sickness) and Leishmania (leishmaniasis) can fulfill heme requirement by receptor-mediated endocytosis of host hemoglobin. However, the mechanism used to transfer hemoglobin-derived heme from the lysosome to the cytosol remains unknown. Here we provide strong evidence that HRG transporters mediate this essential step. In bloodstream T. brucei, TbHRG localizes to the endolysosomal compartment where endocytosed hemoglobin is known to be trafficked. TbHRG overexpression increases cytosolic heme levels whereas its down-regulation is lethal for the parasites unless they express the Leishmania orthologue LmHR1. LmHR1, known to be an essential plasma membrane protein responsible for the uptake of free heme in Leishmania, is also present in its acidic compartments which colocalize with endocytosed hemoglobin. Moreover, LmHR1 levels modulated by its overexpression or the abrogation of an LmHR1 allele correlate with the mitochondrial bioavailability of heme from lysosomal hemoglobin. In addition, using heme auxotrophic yeasts we show that TbHRG and LmHR1 transport hemoglobin-derived heme from the digestive vacuole to the cytosol. Collectively, these results show that trypanosomatid parasites rescue heme from endocytosed hemoglobin through endolysosomal HRG transporters, which could constitute novel drug targets.es_ES
dc.description.sponsorshipWe thank Ivan Hapala (IABG-SAS, Slovakia), Stephen M.Beverley (Washington University School of Medicine, USA)and Olivier Cagnac (EEZ-CSIC, Spain) for kindly providing,respectively, thehem1Dyeast strain, theLeishmaniaandthe yeast vectors used throughout this research work. Wethank Ignacio Perez-Victoria for the preparation of ApoHb.We are grateful to Jean Mathieu Bart (IPBLN-CSIC, Spain)for helpful discussions. This work was supported by Span-ish grants BIO1786 (JMPV) from the Junta de Andalucıa and SAF2011-28215 (JMPV) and BFU2014-55193-P (AE)from the Ministerio de Economıa y Competitividad and by FEDER funds from the EU to JMPV and AE. MCD was astudent of the PhD program “Biochemistry and MolecularBiology” of the University of Granada (Spain). MCD was recipient of a FPU fellowship from the Spanish Ministerio de Educacion, Cultura y Deporte; SMC was recipient of a JAE-DOC from the Spanish CSIC (Ministerio de Economıa y Competitividad), cofounded by the Fondo Social Europeo,LMOZ was recipient of a Colciencias fellowship from the Colombian Ministerio de Ciencia, Tecnologıa e Innovacion;MMG was recipient of a FPI fellowship from the Spanish Ministerio de Economıa y Competitividad. The authorsdeclare that they have no conflict of interestes_ES
dc.publisherJohn Wiley & Sonses_ES
dc.titleTrypanosomatid parasites rescue heme from endocytosed hemoglobin through lysosomal HRG transporterses_ES
dc.description.peerreviewedPeer reviewedes_ES
dc.contributor.funderJunta de Andalucíaes_ES
dc.contributor.funderMinisterio de Economía y Competitividad (España)es_ES
dc.contributor.funderEuropean Commissiones_ES
dc.contributor.funderMinisterio de Educación, Cultura y Deporte (España)es_ES
dc.contributor.funderColciencias (Colombia)es_ES
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