Formins (FHOS) in CD21-mediated signaling & virus entry

CD21 介导的信号传导中的福尔明 (FHOS)

• 批准号: 7370985
• 负责人: JOYCE DIANE FINGEROTH
• 金额: $ 35.58万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7370985
• 关键词: Achievement; Actin-Binding Protein; Actins; Affinity; Amino Acids; Antigens; Autoimmune Diseases; B-Lymphocytes; Binding; Binding Proteins; CD19 gene; Cancer Vaccine Related Development; Cell Lineage; Cell Polarity; Cell membrane; Cell surface; Cells; Communicable Diseases; Complement 3d Receptors; Complement Receptor; Complex; Cytoplasm; Cytoplasmic Protein; Cytoplasmic Tail; Cytoskeletal Modeling; DNA Sequence Rearrangement; Data; Development; Distal; Epithelial Cells; Epstein-Barr Virus Infections; Evolution; Excision; Family; Filtration; Gene Expression; Genetic Transcription; Goals; Guanosine Triphosphate Phosphohydrolases; HIV; Homologous Gene; Human; Human Herpesvirus 4; Immune response; Immune system; In Vitro; Investigation; Knowledge; Lead; Ligands; Ligation; Link; Localized; Malignant Neoplasms; Mediating; Membrane; Molecular; Morphogenesis; Pathogenesis; Pathway interactions; Pattern; Play; Post-Translational Protein Processing; Protein Overexpression; Proteins; Recruitment Activity; Reporting; Role; Scaffolding Protein; Serum; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Spleen; Splenic Red Pulp; Stimulus; Testing; Viral; Virus; base; complement C3d,g; extracellular; human disease; in vivo; link protein; member; novel; pathogen; polymerization; profilin; protein function; receptor; rho; scaffold; src-Family Kinases; transmission process

DESCRIPTION (provided by applicant): Human CD21 is an innate immune system receptor (C3dg receptor or complement receptor type 2, CR2) and is a key modulator of the acquired immune response. CD21 is also the high affinity receptor for EBV. CD21 plays a direct role in the pathogenesis of a broad spectrum of human disease, including autoimmune disease, infectious disease (EBV and HIV) and cancer. On B cells, CD21 complexes with the major signal transduction regulator CD19, and it is controversial whether CD21 can signal independently of CD19. Although CD21 was identified more than 20 years ago and distinct roles as an attachment protein for C3dg, CD23 and EBV have been discovered, the precise mechanisms enabling CD21 to directly relay information between the exterior and the interior of the cell are unresolved. In Preliminary Studies, FHOS/FHQD a member of the formin family, was found to bind the cytoplasmic domain of human CD21 both in vitro and in vivo. When expressed in epithelial cells (CD19 negative), EGFP-FHOS localized to the cytoplasm and accumulated with actin in membrane protrusions. Remarkably, when CD21 on epithelial cells was ligated with either EBV or anti-CD21, FHOS translocated to the plasma membrane, where it co-localized in aggregates with CD21. Formins are scaffolding proteins that regulate cell polarity and morphogenesis by linking signal transduction to cytoskeletal rearrangement and gene transcription. Recently, formins were discovered to directly nucleate actin by a pathway distinct from the classic Arp 2,3 complex. Based on these observations it is proposed that ligand stimulation of CD21-FHOS interaction transduces intracellular signals through a pathway directed by formin (FHOSV-mediated cytoskeletal reorganization). The goals of Aim I are to identify the amino acid residues that mediate interaction between CD21 and FHOS and to screen for novel FHOS/CD21-binding proteins as potential downstream effectors of this pathway. Aim II is focused on determining whether FHOS directly nucleates actin, and assessing the role of CD21 in FHOS activation, actin polymerization, and signaling. The goals of Aim III are to isolate and characterize the splenic littoral cell, a specialized cell abundant in human red pulp that highly expresses FHOS, CD21 and is believed to function in antigen filtration. Achievement of these Aims will provide important new knowledge about how CD21 signals and will elucidate the role(s) of the recently discovered formin protein, FHOS, in the immune system. These investigations may lead to identification of novel targets for treatment of autoimmune disease and cancer, for development of vaccines and for eradication of persistent viral and bacterial pathogens that are sequestered by CD21.

描述（由申请人提供）：人CD 21是一种先天性免疫系统受体（C3 dg受体或补体受体2型，CR2），是获得性免疫应答的关键调节剂。CD 21也是EBV的高亲和力受体。CD 21在多种人类疾病的发病机制中起直接作用，包括自身免疫性疾病、感染性疾病（EBV和HIV）和癌症。 在B细胞上，CD 21与主要的信号转导调节因子CD 19复合，并且CD 21是否能够独立于CD 19而进行信号传导是有争议的。 虽然CD 21在20多年前就被发现，并且已经发现了CD 21作为C3 dg、CD 23和EBV的附着蛋白的不同作用，但使CD 21能够在细胞外部和内部之间直接传递信息的精确机制尚未得到解决。在初步研究中，发现FHOS/FHQD是CD 21家族的成员，在体外和体内均与人CD 21的胞质结构域结合。 当在上皮细胞（CD 19阴性）中表达时，EGFP-FHOS定位于细胞质并与肌动蛋白一起积聚在膜突起中。值得注意的是，当上皮细胞上的CD 21与EBV或抗CD 21连接时，FHOS易位到质膜，在那里它与CD 21共定位在聚集体中。 形成蛋白是一种骨架蛋白，通过连接信号转导、细胞骨架重排和基因转录来调节细胞极性和形态发生。 最近，发现formin通过不同于经典的阿普2，3复合物的途径直接使肌动蛋白成核。 基于这些观察结果，提出了配体刺激CD 21-FHOS相互作用通过FHOSV介导的细胞骨架重组（FHOSV介导的细胞骨架重组）指导的途径转导细胞内信号。目的I的目标是鉴定介导CD 21和FHOS之间相互作用的氨基酸残基，并筛选新的FHOS/CD 21结合蛋白作为该途径的潜在下游效应物。目的二是确定FHOS是否直接成核肌动蛋白，并评估CD 21在FHOS活化，肌动蛋白聚合和信号转导中的作用。目的III的目标是分离和表征脾沿岸的细胞，这是一种在人红髓中丰富的特化细胞，高度表达FHOS、CD 21，并被认为在抗原过滤中起作用。这些目标的实现将提供关于CD 21如何信号传导的重要新知识，并将阐明最近发现的CD 21蛋白FHOS在免疫系统中的作用。这些研究可能导致识别用于治疗自身免疫性疾病和癌症的新靶点，用于开发疫苗和根除由CD 21隔离的持久性病毒和细菌病原体。