A lipocalin mediates unidirectional heme biomineralization in malaria parasites

Matz, J.M.; Drepper, B.; Blum, T.B.; Genderen, E. van; Burrell, A.; Martin, P.; Stach, T.; Collinson, L.M.; Abrahams, J.P.; Matuschewski, K.; Blackman, M.J.

doi:doi:10.1073/pnas.2001153117

During blood-stage development, malaria parasites are challenged with the detoxification of enormous amounts of heme released during the proteolytic catabolism of erythrocytic hemoglobin. They tackle this problem by sequestering heme into bioinert crys-tals known as hemozoin. The mechanisms underlying this biomi-neralization process remain enigmatic. Here, we demonstrate that both rodent and human malaria parasite species secrete and in-ternalize a lipocalin-like protein, PV5, to control heme crystalliza-tion. Transcriptional deregulation of PV5 in the rodent parasite Plasmodium berghei results in inordinate elongation of hemozoin crystals, while conditional PV5 inactivation in the human malaria agent Plasmodium falciparum causes excessive multidirectional crystal branching. Although hemoglobin processing remains unaf-fected, PV5-deficient parasites generate less hemozoin. Electron diffraction analysis indicates that despite the distinct changes in crystal morphology, neither the...Show moreDuring blood-stage development, malaria parasites are challenged with the detoxification of enormous amounts of heme released during the proteolytic catabolism of erythrocytic hemoglobin. They tackle this problem by sequestering heme into bioinert crys-tals known as hemozoin. The mechanisms underlying this biomi-neralization process remain enigmatic. Here, we demonstrate that both rodent and human malaria parasite species secrete and in-ternalize a lipocalin-like protein, PV5, to control heme crystalliza-tion. Transcriptional deregulation of PV5 in the rodent parasite Plasmodium berghei results in inordinate elongation of hemozoin crystals, while conditional PV5 inactivation in the human malaria agent Plasmodium falciparum causes excessive multidirectional crystal branching. Although hemoglobin processing remains unaf-fected, PV5-deficient parasites generate less hemozoin. Electron diffraction analysis indicates that despite the distinct changes in crystal morphology, neither the crystalline order nor unit cell of hemozoin are affected by impaired PV5 function. Deregulation of PV5 expression renders P. berghei hypersensitive to the antima-larial drugs artesunate, chloroquine, and atovaquone, resulting in accelerated parasite clearance following drug treatment in vivo. Together, our findings demonstrate the Plasmodium-tailored role of a lipocalin family member in hemozoin formation and under-score the heme biomineralization pathway as an attractive target for therapeutic exploitation.Show less

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A lipocalin mediates unidirectional heme biomineralization in malaria parasites