A novel family of Toxoplasma IMC proteins displays a hierarchical organization and functions in coordinating parasite division.
A novel family of Toxoplasma IMC proteins displays a hierarchical organization and functions in coordinating parasite division.
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弓形虫 IMC 蛋白的一个新家族在协调寄生虫分裂中表现出层次结构和功能。
DOI：
10.1371/journal.ppat.1001094
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发表时间：
2010-09-09
期刊：
影响因子：
6.7
通讯作者：
Bradley, Peter J.
中科院分区：
文献类型：
--
作者：
Beck, Josh R.;Rodriguez-Fernandez, Imilce A.;de Leon, Jessica Cruz;Huynh, My-Hang;Carruthers, Vern B.;Morrissette, Naomi S.;Bradley, Peter J.
顶复门利用称为内膜复合体（IMC）的外周膜系统进行关键过程，如宿主细胞入侵和子细胞形成。我们已经确定了一个家庭的蛋白质，定义新的亚区室的弓形虫IMC。这些IMC亚隔室蛋白，ISP 1，2和3，在整个顶复门中是保守的，但似乎不存在于门外。ISP 1定位于IMC的顶帽部分，而ISP 2定位于中央IMC区域，ISP 3定位于复合物的中央加基底区域。所有三种ISP的靶向依赖于预测用于协调肉豆蔻酰化和棕榈酰化的N-末端残基。令人惊讶的是，我们表明，中断的ISP 1的结果在一个戏剧性的重新定位的ISP 2和ISP 3的顶帽。尽管ISP 1的N-末端区域对于顶帽靶向是必需且足够的，但排除其他家族成员需要蛋白质的剩余C-末端区域。ISP 1的这种守门功能揭示了一种前所未有的蛋白质相互作用和分级靶向机制，以在弓形虫IMC中建立这些独特的亚室。最后，我们表明，ISP 2的损失导致严重缺陷的子细胞形成过程中endodyphase，表明ISP蛋白在协调这一独特的过程中的作用弓形虫复制。顶复门是人类和动物的重要疾病的原因，包括每年夺去超过一百万人生命的疟疾（恶性疟原虫）和导致出生缺陷和神经系统疾病的弓形虫病（弓形虫）。这些寄生虫拥有一个独特的皮质系统的膜囊排列在细胞骨架网，统称为内膜复合体（IMC）。IMC是宿主入侵所必需的滑行运动机制的锚点，也是复制过程中构建新寄生虫的支架。在这里，我们已经发现了新的见解，通过识别和表征ISP 1 -3，一个家庭的蛋白质，定义新的亚隔间内的弓形虫IMC的组织和功能。预测的肉豆蔻酰化和棕榈酰化的残基在这些蛋白质的膜靶向中是至关重要的，这表明多个棕榈酰酰基转移酶活性存在于IMC内并决定其组织。令人惊讶的是，ISP 1是ISP 2和3的适当亚室分选所必需的，揭示了这种膜系统组织的新的分级靶向机制。ISP 2的破坏导致内分泌缺陷和寄生虫适应性的急剧丧失，揭示了ISP蛋白在协调寄生虫复制中起着重要作用。
Apicomplexans employ a peripheral membrane system called the inner membrane complex (IMC) for critical processes such as host cell invasion and daughter cell formation. We have identified a family of proteins that define novel sub-compartments of the Toxoplasma gondii IMC. These IMC Sub-compartment Proteins, ISP1, 2 and 3, are conserved throughout the Apicomplexa, but do not appear to be present outside the phylum. ISP1 localizes to the apical cap portion of the IMC, while ISP2 localizes to a central IMC region and ISP3 localizes to a central plus basal region of the complex. Targeting of all three ISPs is dependent upon N-terminal residues predicted for coordinated myristoylation and palmitoylation. Surprisingly, we show that disruption of ISP1 results in a dramatic relocalization of ISP2 and ISP3 to the apical cap. Although the N-terminal region of ISP1 is necessary and sufficient for apical cap targeting, exclusion of other family members requires the remaining C-terminal region of the protein. This gate-keeping function of ISP1 reveals an unprecedented mechanism of interactive and hierarchical targeting of proteins to establish these unique sub-compartments in the Toxoplasma IMC. Finally, we show that loss of ISP2 results in severe defects in daughter cell formation during endodyogeny, indicating a role for the ISP proteins in coordinating this unique process of Toxoplasma replication. Apicomplexans are the cause of important diseases in humans and animals including malaria (Plasmodium falciparum), which claims over a million human lives each year, and toxoplasmosis (Toxoplasma gondii), which causes birth defects and neurological disorders. These parasites possess a unique cortical system of membrane sacs arranged on a cytoskeletal meshwork, together referred to as the inner membrane complex (IMC). The IMC is the anchor point for the gliding motility machinery necessary for host invasion and also a scaffold around which new parasites are constructed during replication. Here we have uncovered new insights into the organization and function of this structure by identifying and characterizing ISP1-3, a family of proteins that define novel sub-compartments within the Toxoplasma IMC. Residues predicted for myristoylation and palmitoylation are critical in the membrane targeting of these proteins, suggesting that multiple palmitoyl acyltransferase activities reside within the IMC and dictate its organization. Surprisingly, ISP1 is required for proper sub-compartment sorting of ISP2 and 3, revealing a novel hierarchical targeting mechanism for the organization of this membrane system. Disruption of ISP2 results in defects during endodyogeny and a dramatic loss in parasite fitness, revealing that the ISP proteins play an important role in coordinating parasite replication.
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