Trypanosomatid parasites rescue heme from endocytosed hemoglobin through lysosomal HRG transporters.
Pathogenic 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 downregulation 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.
Instituto de Parasitología y Biomedicina "López-Neyra", CSIC, (IPBLN-CSIC), PTS Granada, Avda. del Conocimiento s/n, Granada, 18016, Spain.
María
M
Cabello-Donayre
Instituto de Parasitología y Biomedicina "López-Neyra", CSIC, (IPBLN-CSIC), PTS Granada, Avda. del Conocimiento s/n, Granada, 18016, Spain.
Sophie
S
Malagarie-Cazenave
Instituto de Parasitología y Biomedicina "López-Neyra", CSIC, (IPBLN-CSIC), PTS Granada, Avda. del Conocimiento s/n, Granada, 18016, Spain.
Jenny
J
Campos-Salinas
Instituto de Parasitología y Biomedicina "López-Neyra", CSIC, (IPBLN-CSIC), PTS Granada, Avda. del Conocimiento s/n, Granada, 18016, Spain.
Francisco J
FJ
Gálvez
Instituto de Parasitología y Biomedicina "López-Neyra", CSIC, (IPBLN-CSIC), PTS Granada, Avda. del Conocimiento s/n, Granada, 18016, Spain.
Alba
A
Rodríguez-Martínez
Instituto de Parasitología y Biomedicina "López-Neyra", CSIC, (IPBLN-CSIC), PTS Granada, Avda. del Conocimiento s/n, Granada, 18016, Spain.
Estela
E
Pineda-Molina
Instituto de Parasitología y Biomedicina "López-Neyra", CSIC, (IPBLN-CSIC), PTS Granada, Avda. del Conocimiento s/n, Granada, 18016, Spain.
Lina M
LM
Orrego
Instituto de Parasitología y Biomedicina "López-Neyra", CSIC, (IPBLN-CSIC), PTS Granada, Avda. del Conocimiento s/n, Granada, 18016, Spain.
Marta
M
Martínez-García
Instituto de Parasitología y Biomedicina "López-Neyra", CSIC, (IPBLN-CSIC), PTS Granada, Avda. del Conocimiento s/n, Granada, 18016, Spain.
María P
MP
Sánchez-Cañete
Instituto de Parasitología y Biomedicina "López-Neyra", CSIC, (IPBLN-CSIC), PTS Granada, Avda. del Conocimiento s/n, Granada, 18016, Spain.
Antonio M
AM
Estévez
Instituto de Parasitología y Biomedicina "López-Neyra", CSIC, (IPBLN-CSIC), PTS Granada, Avda. del Conocimiento s/n, Granada, 18016, Spain. josepv@ipb.csic.es.
José M
JM
Pérez-Victoria
D000595:Amino Acid Sequence; D000818:Animals; D003600:Cytosol / Q000378:metabolism; D004705:Endocytosis / Q000502:physiology; D006418:Heme / Q000378:metabolism*; D006454:Hemoglobins / Q000378:metabolism*; D007891:Leishmania / Q000378:metabolism; D007896:Leishmaniasis / Q000097:blood / Q000378:metabolism* / Q000469:parasitology*; D008247:Lysosomes / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D021381:Protein Transport; D015800:Protozoan Proteins / Q000378:metabolism; D014346:Trypanosoma brucei brucei / Q000378:metabolism* / Q000469:parasitology
D006454:Hemoglobins; D026901:Membrane Transport Proteins; D015800:Protozoan Proteins; D006418:Heme