ER-shaping proteins of Plasmodium

疟原虫的内质网塑造蛋白

• 批准号: 10240941
• 负责人: Purnima Bhanot
• 金额: $ 66.84万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10240941
• 关键词: Affect; Anabolism; Antimalarials; Architecture; Attenuated; Biological; Cell membrane; Cells; Collection; Cytoplasm; Data; Defect; Development; Dissection; Drug resistance; Endoplasmic Reticulum; Environment; Equilibrium; Erythrocytes; Eukaryota; Eukaryotic Cell; Family; Future; Genes; Goals; Growth; Guanosine Triphosphate Phosphohydrolases; Hemoglobin; Hepatic; Hepatocyte; Homologous Gene; Immunity; In Vitro; Individual; Infection; Knowledge; Length; Life Style; Link; Liver; Malaria; Mammalian Cell; Mass Spectrum Analysis; Membrane; Microscopy; Molecular; Morphogenesis; Morphology; Mus; Mutation; Nutrient; Organelles; Outcome; Parasites; Pathogenicity; Pattern; Peptides; Physiology; Plant Proteins; Plasmodium; Plasmodium berghei; Play; Process; Protein Export Pathway; Protein Secretion; Proteins; Proteome; Protozoa; RTN1 gene; Resistance; Resolution; Role; Shapes; Specific qualifier value; Structure; Structure-Activity Relationship; Surface; Tertiary Protein Structure; Time; Tubular formation; Vacuole; Work; Yeasts; asexual; base; drug development; in vivo; insight; intrahepatic; knock-down; knockout gene; mRNA Expression; malformation; new therapeutic target; novel; parasitism; protein transport; residence; resistance mechanism; small molecule; solute; spatiotemporal; trafficking

ABSTRACT The endoplasmic reticulum (ER) of eukaryotic cells is an essential organelle with many critical functions including, protein secretion. Its function is closely tied to its morphology. Work in higher eukaryotes has shown that mutations in key proteins required to generate the ER tubular network cause specific growth and developmental defects. In contrast to higher eukaryotes, little is known of how the ER is shaped in early eukaryotes such as protozoa. ER structure in the protozoan parasite, Plasmodium is dynamic and stage-specific but its molecular determinants are unknown. To understand how the ER acquires its shape in different stages of Plasmodium, we identified homologs of key ER-shaping proteins including ones that contain a reticulon homology domain. One of these protein induces membrane curvature in vitro. P. berghei parasites lacking the protein have dysmorphic ER, an enlarged digestive vacuole, are severely attenuated in the asexual cycle but infect hepatocytes normally. We hypothesize that the putative Plasmodium ER-shaping proteins we identified have stage-specific roles in maintaining proper ER structure/function. This proposal will determine the contributions of these proteins in shaping the ER of erythrocytic and hepatic stages of Plasmodium, using morphological and ultrastructural studies of P. berghei gene-knockouts. It will determine the effect of their loss on a key ER function, protein trafficking in the parasite. Our study will provide the first causal link between ER architecture, protein trafficking and the ability of the malaria parasite to reside in different host environments.

抽象的 真核细胞的内质网（ER）是必不可少的细胞器，具有许多关键功能 包括蛋白质分泌。它的功能与其形态密切相关。在高等真核生物中的工作已显示 产生ER管网所需的关键蛋白质突变会导致特定的增长和 发展缺陷。与较高的真核生物相反，对ER在早期的形状几乎一无所知 真核生物，例如原生动物。 原生动物寄生虫中的ER结构，疟原虫是动态和特异性的，但其分子是 决定因素是未知的。要了解急诊室如何在不同质量的不同阶段获得其形状， 我们确定了关键ER成型蛋白的同源物，其中包括包含网状同源性域的蛋白质。 这些蛋白质之一会在体外诱导膜曲率。 P. berghei寄生虫缺乏蛋白质 畸形ER是一种扩大的消化液泡，在无性周期中严重减弱，但感染 肝细胞通常。我们假设我们发现的假定的质子质质质质蛋白具有 在维持适当的ER结构/功能方面的特定角色。该建议将确定贡献 使用形态和 P. berghei基因敲除的超微结构研究。它将确定他们损失对钥匙ER的影响 功能，寄生虫中的蛋白质运输。我们的研究将提供ER体系结构之间的第一个因果关系， 蛋白质运输和疟原虫居住在不同宿主环境中的能力。