10779/crick.12662054.v1
Joachim M Matz
Joachim M
Matz
Benjamin Drepper
Benjamin
Drepper
Thorsten B Blum
Thorsten B
Blum
Eric van Genderen
Eric
van Genderen
Alana Burrell
Alana
Burrell
Peer Martin
Peer
Martin
Thomas Stach
Thomas
Stach
Lucy M Collinson
Lucy M
Collinson
Jan Pieter Abrahams
Jan Pieter
Abrahams
Kai Matuschewski
Kai
Matuschewski
Michael J Blackman
Michael J
Blackman
A lipocalin mediates unidirectional heme biomineralization in malaria parasites.
The Francis Crick Institute
2020
PV5
Plasmodium
hemozoin
lipocalin
malaria
Blackman FC001043
LM-ack
EM
2020-07-16 12:41:43
Journal contribution
https://crick.figshare.com/articles/journal_contribution/A_lipocalin_mediates_unidirectional_heme_biomineralization_in_malaria_parasites_/12662054
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 crystals known as hemozoin. The mechanisms underlying this biomineralization process remain enigmatic. Here, we demonstrate that both rodent and human malaria parasite species secrete and internalize a lipocalin-like protein, PV5, to control heme crystallization. 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 unaffected, 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 antimalarial 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 underscore the heme biomineralization pathway as an attractive target for therapeutic exploitation.