HIV-1 Vif in AIDS-Related Malignancies

HIV-1 Vif 在艾滋病相关恶性肿瘤中的作用

基本信息

批准号：
9751250
负责人：
Adam Z Cheng
金额：
$ 4.64万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9751250
关键词：
AIDS related cancer Affinity Chromatography Apoptosis Automobile Driving Autophagocytosis Binding Biological Markers CD4 Positive T Lymphocytes CUL4A gene CUL5 gene Cell Cycle Arrest Cell Death Cell physiology Cells Complex Data Dose Feline Immunodeficiency Virus Fellowship Gene Expression HIV HIV Infections HIV-1 Impairment Infection Knowledge Ligase Light Malignant Neoplasms Maps Mass Spectrum Analysis Mediating Metabolic One-Step dentin bonding system Pathogenesis Pathway interactions Phenotype Polyubiquitination Post-Translational Protein Processing Process Protein Family Proteins Publications Regulation Role SIV Screening for cancer Site-Directed Mutagenesis Structure Subfamily lentivirinae Testing Therapeutic Intervention Ubiquitination Viral Viral Packaging Viral Physiology Work cofactor inhibition of autophagy new therapeutic target novel particle protein complex protein degradation public health relevance recruit transcription factor tumor tumorigenesis ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): HIV-1 Vif in AIDS-Related Malignancies ABSTRACT Viral infectivity factor (Vif) is an accessory protein found in nearly all lentiviruses including HV-1 and is essential for productive infection in CD4+ T cells. Its canonical function revolves around the APOBEC3-Vif axis, whereby Vif polyubiquitinates and targets APOBEC3 proteins for degradation by hijacking the transcription factor CBFß and an E3 ubiquitin ligase containing CUL5, ELOB, ELOC, and RBX2. However, numerous data suggest that Vif possesses alternative functions. Recently, we have found that Vif also interacts with the autophagy-related protein, AMBRA1, and that this Vif-AMBRA1 interaction is conserved among HIV-1, SIV, FIV, BIV, and MVV. Conservation alone suggests a novel alternative Vif function. Vif most likely hijacks AMBRA1 from its normal functions in apoptosis and autophagy and forms an E3 ubiquitin ligase to degrade cellular proteins. Aim 1 of this proposal will focus on identifying the complete Vif-AMBRA1 interacting complex by 1A) using a validated tandem affinity purification-mass spectrometry approach and 1B) mapping the interaction domains of each constituent via systematic truncation and site-directed mutagenesis. Aim 2 of this proposal will explore the function of the Vif-AMBRA1 complex by 2A) quantifying the impact of Vif on AMBRA1- mediated autophagy and apoptosis and 2B) identifying the cellular ubiquitination targets of the Vif-AMBRA1 ligase complex. The studies proposed here may provide an additional mechanism of tumorigenesis during HIV infection. As is with all tumors, no one-step process directly explains AIDS-related malignancies, but combinations of factors such as subversion of host proteins and modulation of cellular processes serve as important steps in this complex process.

描述（通过应用程序证明）：与AIDS相关的恶性肿瘤中的HIV-1 VIF抽象病毒感染因子（VIF）是几乎所有慢病毒在内的辅助蛋白ND，包括HV-1，对于CD4+ TELS中的生产力是必不可少的。 -VIF轴，VIF多泛素化apobets apobets apobec3蛋白通过cbfß降解，而e3 ubiquitin rigase contencon contercon cul5，elob，elob，elob，elob，eloc和rbx2也发现了vif。这种VIF-AMBR1相互作用是保守的HIV-1 V，BIV和MVV。确定使用经过验证的串联亲和力纯度质谱法和1B的完整VIF-AMBRA1相互作用，并通过系统截断和位置定向的诱变将每个组成部分的相互作用域绘制。 -AMBRA1通过2A）对Ambra1介导的自噬和凋亡的影响，VIF-AMBRA1连接酶复合物的凋亡2b TS。一步过程，与AIDS相关的恶性肿瘤，但颠覆宿主素调制的因素组合是该复杂过程中的重要步骤。