The role of Plasmodium V-ATPase in vacuolar physiology and antimalarial drug uptake.
The role of Plasmodium V-ATPase in vacuolar physiology and antimalarial drug uptake.
复制标题
DOI：
10.1073/pnas.2306420120
复制
发表时间：
2023-07-25
影响因子：
11.1
通讯作者：
Matz, Joachim M.
中科院分区：
文献类型：
--
作者：
Alder, Arne;Sanchez, Cecilia P.;Russell, Matthew R. G.;Collinson, Lucy M.;Lanzer, Michael;Blackman, Michael J.;Gilberger, Tim-Wolf;Matz, Joachim M.
疟疾是由疟原虫引起的，这种寄生虫在人类红细胞内复制。在红细胞内生长期间，寄生虫在酸化的空泡中吸收和消化宿主细胞的血红蛋白。几种抗疟药干扰了这个液泡中的生化途径，导致寄生虫死亡。长期以来，人们一直认为，这些药物的积累仅仅是寄生虫胞浆和液泡腔之间的pH梯度的函数。通过靶向为这种梯度提供动力的多聚质子泵，我们确定了这种蛋白质复合体在生理和维持消化液泡方面的不同功能。与目前的看法相反，我们发现质子梯度的严重消散对抗疟疾药物的摄取只有有限的影响，而对药物敏感性没有影响。为了确保它们在人类血液中的生存，疟疾寄生虫在酸化的消化液泡中降解高达80%的宿主红细胞血红蛋白。在这里，我们结合条件反向遗传学和定量成像方法来证明人类疟疾病原体恶性疟原虫利用一个异多聚体V-ATPase复合体来酸化消化的空泡基质，这对于空泡内血红蛋白的释放、血红素的解毒和寄生虫的生存是必不可少的。我们揭示了膜包埋的V-ATPase亚单位在调节消化液泡的形态发生方面不依赖于质子转运的额外功能。我们进一步表明，抗疟疾化疗药物在空泡内的积累对空泡的严重脱酸具有惊人的弹性，并且V-ATPase活性的调节不会影响寄生虫对这些药物的敏感性。
Malaria is caused by Plasmodium parasites, which replicate within human erythrocytes. During intraerythrocytic growth, the parasite takes up and digests host cell hemoglobin in an acidified vacuole. Several antimalarials interfere with biochemical pathways in this vacuole leading to parasite death. It was long believed that accumulation of these drugs is a mere function of the pH gradient between parasite cytosol and the vacuolar lumen. By targeting the multimeric proton pump powering this gradient, we identify distinct functions of this protein complex in physiology and maintenance of the digestive vacuole. Contrary to current belief, we find that severe dissipation of the proton gradient has only limited impact on antimalarial drug uptake and no effect on drug susceptibility. To ensure their survival in the human bloodstream, malaria parasites degrade up to 80% of the host erythrocyte hemoglobin in an acidified digestive vacuole. Here, we combine conditional reverse genetics and quantitative imaging approaches to demonstrate that the human malaria pathogen Plasmodium falciparum employs a heteromultimeric V-ATPase complex to acidify the digestive vacuole matrix, which is essential for intravacuolar hemoglobin release, heme detoxification, and parasite survival. We reveal an additional function of the membrane-embedded V-ATPase subunits in regulating morphogenesis of the digestive vacuole independent of proton translocation. We further show that intravacuolar accumulation of antimalarial chemotherapeutics is surprisingly resilient to severe deacidification of the vacuole and that modulation of V-ATPase activity does not affect parasite sensitivity toward these drugs.
登录
查看更多内容
影响因子：
5.3
作者：
Jida, Mouhamad;Sanchez, Cecilia P.;Davioud-Charvet, Elisabeth
通讯作者：
Davioud-Charvet, Elisabeth
影响因子：
2.3
作者：
Lew, VL;Macdonald, L;Tiffert, T
通讯作者：
Tiffert, T
影响因子：
30.3
作者：
Mesen-Ramirez, Paolo;Bergmann, Baerbel;Spielmann, Tobias
通讯作者：
Spielmann, Tobias
影响因子：
20.3
作者：
deDominguez, NDG;Rosenthal, PJ
通讯作者：
Rosenthal, PJ
影响因子：
5.8
作者：
GEARY, TG;JENSEN, JB;GINSBURG, H
通讯作者：
GINSBURG, H