Characterization of the antiviral activity of BCA2

BCA2 抗病毒活性的表征

基本信息

批准号：
8728540
负责人：
Ruth Serra Moreno
金额：
$ 2万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8728540
关键词：
Address Affect Agreement Animal Viruses Anti-Retroviral Agents Antiviral Agents Antiviral Therapy Binding Breast Cancer Cell Cancer cell line Cells Cytoplasm Cytoplasmic Tail Development Endocytosis Ensure Estrogens Fingers Gagging Gene Expression Profiling Genes Goals Gray unit of radiation dose HIV HIV-1 HIV-2 Human Immune Targeting Individual Infection Inflammatory Integral Membrane Protein Interferons Mammalian Cell Mediating Modeling Molecular Molecular Profiling Pathogenesis Pathway interactions Pharmaceutical Preparations Predisposition Primate Lentiviruses Process Production Promoter Regions Proteins Regulation Reporting Resolution Response Elements Role SIV Signal Transduction Testing Time Ubiquitination Up-Regulation Viral Viral Proteins Virion Virus Virus Assembly Virus Inhibitors Virus Replication Wound Healing antiretroviral therapy chemokine cytokine gag Gene Products malignant breast neoplasm novel particle pathogen public health relevance response ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): BCA2 (Breast Cancer-Associated gene 2, also known as RNF115, ZNF364 or Rabring7) is a RING-finger E3 ubiquitin ligase that is up-regulated in most breast cancer cell lines in response to estrogen. A recent study showed that BCA2 interacts with the cytoplasmic domain of tetherin to promote the internalization and lysosomal degradation of tethered HIV-1 particles, and that the E3 ligase activity of BCA2 is dispensable to enhance the tetherin-mediated restriction of HIV-1. Therefore, BCA2 would act as a tetherin co-factor, lacking antiviral activity in cells that do not express tetherin. However, here we show, fo the first time, that BCA2 inhibits virus production in a tetherin-independent manner by reducing the cellular levels of HIV-1 Gag, and that this activity requires an intact RING-finger domain. Furthermore, we show that BCA2 physically interacts with Gag and promotes its ubiquitination and lysosomal degradation, suggesting that BCA2 may be an innate antiviral factor that interferes with virus assembly. We want to formally address this hypothesis by characterizing the molecular mechanisms of the antiviral activity of BCA2 (Specific Aim 1) and by identifying the molecules that participate in the regulation of BCA2's activity, as well as the cellular pathways that are activated in response to BCA2 (Specific Aim 2). A better understanding of the innate mechanisms that limit virus production will help in the elaboration of antiretroviral drugs o contain virus replication in affected individuals. Therefore, the objectives outlined here are directly relevant to identifying new targets for antiretroviral therapy to control HIV-1 infection.

描述（由申请人提供）：BCA2（乳腺癌相关基因 2，也称为 RNF115、ZNF364 或 Rabring7）是一种环指 E3 泛素连接酶，在大多数乳腺癌细胞系中响应雌激素而上调。最近的一项研究表明，BCA2 与 tetherin 的细胞质结构域相互作用，促进束缚的 HIV-1 颗粒的内化和溶酶体降解，并且 BCA2 的 E3 连接酶活性对于增强 tetherin 介导的 HIV-1 限制是必不可少的。因此，BCA2 将充当系链蛋白辅助因子，在不表达系链蛋白的细胞中缺乏抗病毒活性。然而，我们在这里首次表明，BCA2 通过降低 HIV-1 Gag 的细胞水平，以不依赖于系链蛋白的方式抑制病毒产生，并且这种活性需要完整的环指结构域。此外，我们发现BCA2与Gag发生物理相互作用并促进其泛素化和溶酶体降解，这表明BCA2可能是干扰病毒组装的先天抗病毒因子。我们希望通过表征 BCA2 抗病毒活性的分子机制（具体目标 1）并确定参与 BCA2 活性调节的分子以及响应 BCA2 激活的细胞途径来正式解决这一假设。（具体目标 2）。更好地了解限制病毒产生的先天机制将有助于研制抗逆转录病毒药物或抑制受影响个体中的病毒复制。因此，这里概述的目标与确定抗逆转录病毒治疗控制 HIV-1 感染的新靶点直接相关。