Characterization of the antiviral activity of BCA2

BCA2 抗病毒活性的表征

基本信息

批准号：
8926085
负责人：
Ruth Serra Moreno
金额：
$ 19.17万
依托单位：
TEXAS TECH UNIVERSITY
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 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8926085
关键词：
Address Affect Agreement Animal Viruses Anti-Retroviral Agents Antiviral Agents Binding Breast Cancer Cell Cancer cell line Cells Cytoplasmic Tail Estrogens Fingers Gagging Gene Expression Profiling Genes HIV-1 HIV-2 Human Individual Infection Inflammation Integral Membrane Protein Interferon Type I Interferons Life Cycle Stages Mammalian Cell Mediating Molecular Molecular Profiling Pathogenesis Pathway interactions Pharmaceutical Preparations Phosphorylation Post-Translational Protein Processing Primate Lentiviruses Process Production Promoter Regions Proteins Regulation Reporting Resolution Response Elements Role SIV Testing Time Ubiquitination Viral Proteins Virion Virus Virus Assembly Virus Inhibitors Virus Replication Wound Healing antiretroviral therapy chemokine cytokine gag Gene Products malignant breast neoplasm microbial particle response ubiquitin-protein ligase

项目摘要

PROJECT SUMMARY BCA2 (Breast Cancer-Associated gene 2, also known as RNF115, ZNF364 or Rabring7) is a cytoplasmic RING-finger E3 ubiquitin ligase that is upregulated 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 that BCA2 inhibits virus production in a tetherin-independent manner by reducing the cellular levels of HIV-1 Gag, and that this activity requires the E3 ligase activity. Furthermore, we show that BCA2 physically interacts with Gag and promotes its ubiquitination, suggesting that BCA2 may be an innate antiviral factor that targets the Gag polyprotein for degradation, thereby, impeding 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 and cellular pathways that participate in the regulation of BCA2's activity (Specific Aim 2). A better understanding of the innate mechanisms that limit virus production will help in the elaboration of antiretroviral drugs to 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.

项目概要 BCA2（乳腺癌相关基因 2，也称为 RNF115、ZNF364 或 Rabring7）是一种细胞质环指 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。一个最近的研究表明BCA2与tetherin的胞质结构域相互作用以促进内化和束缚的 HIV-1 颗粒的溶酶体降解，并且 BCA2 的 E3 连接酶活性是可有可无的增强 Tetherin 介导的 HIV-1 限制。因此，BCA2 将充当系链素辅助因子，在不表达系链蛋白的细胞中缺乏抗病毒活性。然而，在这里我们表明BCA2抑制病毒通过降低 HIV-1 Gag 的细胞水平，以不依赖于系链蛋白的方式产生，并且这种活性需要 E3 连接酶活性。此外，我们表明 BCA2 与 Gag 发生物理相互作用并促进其泛素化，表明 BCA2 可能是一种针对 Gag 多蛋白的先天抗病毒因子降解，从而阻止病毒组装。我们想通过表征来正式解决这个假设 BCA2 抗病毒活性的分子机制（具体目标 1）并通过识别分子以及参与 BCA2 活性调节的细胞途径（具体目标 2）。更好的了解限制病毒产生的先天机制将有助于抗逆转录病毒药物的制定抑制受影响个体中病毒复制的药物。因此，这里概述的目标直接是与确定抗逆转录病毒治疗控制 HIV-1 感染的新靶标相关。