Intramembrane proteolysis mediates shedding of a key adhesin during erythrocyte invasion by the malaria parasite.
Intramembrane proteolysis mediates shedding of a key adhesin during erythrocyte invasion by the malaria parasite.
复制标题
DOI：
10.1083/jcb.200604136
复制
发表时间：
2006-09-25
影响因子：
7.8
通讯作者：
Blackman, Michael J
中科院分区：
文献类型：
--
作者：
O'Donnell, Rebecca A;Hackett, Fiona;Howell, Steven A;Treeck, Moritz;Struck, Nicole;Krnajski, Zita;Withers-Martinez, Chrislaine;Gilberger, Tim W;Blackman, Michael J
顶复合体病原体是专性细胞内寄生虫。为了进入细胞，它们必须以高亲和力结合宿主细胞受体，然后解除这些相互作用以完成入侵。恶性疟原虫是造成最危险形式疟疾的寄生虫，它的子体利用一种被称为达菲结合配体-红细胞结合蛋白（dbl - ebp）的粘附素家族侵入红细胞。最具特征的恶性疟原虫DBL-EBP是红细胞结合抗原175 (EBA-175)，它与红细胞表面糖蛋白a结合。我们报道EBA-175在入侵点周围从胚子中脱落。脱落发生在跨膜结构域（TMD）的一个保守的位点，在DBL-EBP家族。我们发现EBA-175可以被PfROM4切割，PfROM4是一种定位于分裂子质膜的菱形蛋白酶，而其他菱形蛋白酶则不能。EBA-175 TMD内消除PfROM4切割的突变可阻止寄生虫生长。我们的研究结果确定了在这种病原体的生命周期中膜内蛋白水解的关键作用。
Apicomplexan pathogens are obligate intracellular parasites. To enter cells, they must bind with high affinity to host cell receptors and then uncouple these interactions to complete invasion. Merozoites of Plasmodium falciparum, the parasite responsible for the most dangerous form of malaria, invade erythrocytes using a family of adhesins called Duffy binding ligand-erythrocyte binding proteins (DBL-EBPs). The best-characterized P. falciparum DBL-EBP is erythrocyte binding antigen 175 (EBA-175), which binds erythrocyte surface glycophorin A. We report that EBA-175 is shed from the merozoite at around the point of invasion. Shedding occurs by proteolytic cleavage within the transmembrane domain (TMD) at a site that is conserved across the DBL-EBP family. We show that EBA-175 is cleaved by PfROM4, a rhomboid protease that localizes to the merozoite plasma membrane, but not by other rhomboids tested. Mutations within the EBA-175 TMD that abolish cleavage by PfROM4 prevent parasite growth. Our results identify a crucial role for intramembrane proteolysis in the life cycle of this pathogen.