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.

摘要 内质网（endoplasmic reticulum，ER）是真核细胞的重要细胞器，具有多种重要功能 包括蛋白质分泌。其功能与其形态密切相关。高等真核生物的研究表明 产生ER管状网络所需的关键蛋白质的突变引起特异性生长， 发育缺陷与高等真核生物相反，对ER在早期是如何形成的知之甚少。 真核生物如原生动物。 疟原虫的内质网结构是动态的，具有阶段特异性， 决定因素未知。为了了解ER如何在疟原虫的不同阶段获得其形状， 我们鉴定了关键ER形成蛋白的同源物，包括含有reticulon同源结构域的蛋白。 这些蛋白质之一在体外诱导膜弯曲。伯氏疟原虫缺乏这种蛋白质， 异形内质网是一个扩大的消化泡，在无性周期中严重衰减，但感染 肝细胞正常。我们假设我们鉴定的疟原虫ER形成蛋白具有 在维持适当的ER结构/功能方面的特定阶段角色。该提案将决定捐款额 这些蛋白质在形成疟原虫红细胞期和肝期的ER中的作用， 伯氏疟原虫基因敲除的超微结构研究。它将决定他们的损失对一个关键的急诊室的影响 功能，蛋白质运输在寄生虫。我们的研究将提供ER架构， 蛋白质运输和疟原虫在不同宿主环境中生存的能力。