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.

在血液阶段发育过程中，疟原虫面临着红细胞血红蛋白蛋白水解分解代谢过程中释放的大量血红素解毒的挑战。他们通过将血红素隔离到称为疟原虫色素的生物惰性晶体中来解决这个问题。这种生物矿化过程的潜在机制仍然是个谜。在这里，我们证明啮齿动物和人类疟疾寄生虫物种都分泌并内化脂质运载蛋白样蛋白 PV5，以控制血红素结晶。啮齿类寄生虫伯氏疟原虫中PV5的转录失调会导致疟原虫色素晶体过度伸长，而人类疟疾病原体恶性疟原虫中PV5 的条件性失活会导致过度的多向晶体分支。尽管血红蛋白加工不受影响，但缺乏 PV5 的寄生虫产生的疟原虫色素较少。电子衍射分析表明，尽管晶体形态发生了明显变化，但疟原虫色素的晶序和晶胞均未受到 PV5 功能受损的影响。 PV5表达的失调使伯氏疟原虫对抗疟药物青蒿琥酯、氯喹和阿托伐醌过敏，导致体内药物治疗后寄生虫清除加速。总之，我们的研究结果证明了脂质运载蛋白家族成员在疟原虫色素形成中的疟原虫定制作用，并强调了血红素生物矿化途径作为治疗开发的一个有吸引力的目标。