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Vpr as a Mediator Proteasomal Degradation

Vpr 作为蛋白酶体降解的介体

基本信息

批准号：
8071799
负责人：
Carlos M de Noronha
金额：
$ 1.1万
依托单位：
ALBANY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-01 至 2011-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8071799
关键词：
Affinity Amino Acid Sequence Amino Acids Binding Biological Biological Process Cell Cycle Cell Cycle Arrest Cell Cycle Regulation Cell Nucleus Cells Co-Immunoprecipitations Complex Consensus Cullin 1 Cullin Proteins Cytidine Deaminase Data Disabled Persons Disputes Educational process of instructing Exhibits Exposure to F-Box Proteins Face G2 Phase Geminin Gene Expression Genetic Transcription Genome Goals HIV HIV Infections HIV-1 HIV-2 In Vitro Infection Interferons Interphase Cell Lead Learning Ligands Link Maps Mass Spectrum Analysis Mediating Mediator of activation protein Mitosis Mitotic Molecular Conformation Molecular Weight Nuclear Import Open Reading Frames Outcome Paramyxovirus Pathogenesis Pathogenicity Pathway interactions Patients Peptide Sequence Determination Play Population Primate Lentiviruses Primates Production Proteins Reading Frames Research Personnel Resources Role SIV SKP Cullin F-Box Protein Ligases Sampling Set protein Signal Transduction Signaling Protein Simian parainfluenza virus 5 V protein Specificity System Testing Therapeutic Therapeutic Intervention Ubiquitination Viral Virion Virus Virus Replication Work base cellular targeting combat cullin 4A design in vivo insight macrophage mutant overexpression programs protein degradation receptor research study tool transcription factor ubiquitin ligase uracil-DNA glycosylase viral DNA vpr Gene Products

项目摘要

DESCRIPTION (provided by applicant): The HIV1 protein Vpr is highly conserved hi primary patient isolates and is, in vitro, important for establishing low titer infections in macrophages and enhancing virus replication in dividing cells. How Vpr unctions in these capacities and in vivo remains poorly understood. The importance of Vpr for primate entivirus infections is underscored by the observation that several of these viruses, including HIV2, have duplicated vpr to generate two open reading frames, vpr and vpx. This duplication has permitted divergence and presumably, further optimization of Vpr functions. The duplication also supports the supposition that SLV1 Vpr has at least two functions. Experimental infections in which Vpr/x production has been disabled demonstrate diminished pathogenicity. Our work has focused on discovering the role that HIV1 Vpr plays by dentifying cellular proteins that it engages. We compare these with the proteins targeted by its HIV2 counterparts under the hypothesis that although these proteins have diverged hi sequence, their functions still overlap as should the identity of then* protein partners. Our preliminary studies, employing co- immunoprecipitation and tandem mass spectroscopy, have revealed that HTV1 and 2 Vpr, like the V proteins of some paramyxoviruses, both engage an ubiquitin ligase complex that includes DDB1. We hypothesize that Vpr, like the V proteins, targets anti-viral factors for proteasomal degradation using DDB1 to recrui ubiquitin ligases. SPECIFIC AIM 1 will focus on testing the ability of Vpr to, like the V-proteins, act as an adaptor to the ubiquitin ligase machinery and thereby to promote degradation of Stat signaling proteins, or to function as an intermediate in the previously described Vpr-mediated destruction of uracil-N-glycosylase SPECIFIC AIM 2 will determine how the Vpr interactions with ubiquitin ligase complexes impact HIV infections. SPECIFIC AIM 3 will focus on determining the identity of targets of Vpr-mediated ubiquitilation important for Vpr-mediated cell cycle arrest and examining the normal function of the complexes that Vpr engages to promote ubiquitilation.

描述(申请人提供)：HIV1蛋白VPR在原发患者分离株中高度保守，在体外对建立巨噬细胞的低滴度感染和促进分裂细胞中的病毒复制非常重要。VPR如何在这些能力和体内发挥作用仍然知之甚少。观察到，包括HIV2在内的几种病毒复制了VPR，产生了两个开放阅读框架VPR和VPX，这突显了VPR对灵长类全病毒感染的重要性。这种重复允许了VPR功能的分歧，并可能进一步优化VPR功能。该复制还支持SLV1 VPR至少具有两个功能的假设。在实验感染中，VPR/x的产生已被禁用，显示出致病性降低。我们的工作重点是发现HIV1 VPR通过识别它参与的细胞蛋白所起的作用。我们将这些蛋白质与其HIV2对应物靶向的蛋白质进行了比较，假设尽管这些蛋白质具有不同的hi序列，但它们的功能仍然重叠，当时*蛋白质伙伴的身份也应该如此。我们的初步研究，利用免疫共沉淀和串联质谱学，发现HTV1和2VPR，像一些副粘病毒的V蛋白一样，都与包括DDB1在内的泛素连接酶复合体结合。我们假设，VPR和V蛋白一样，利用DDB1到新的泛素连接酶来靶向蛋白酶体降解的抗病毒因子。特定的目标1将集中于测试VPR的能力，如V-蛋白，作为泛素连接酶机制的适配器，从而促进Stat信号蛋白的降解，或作为先前描述的VPR介导的尿嘧啶-N-糖基酶特异性破坏的中间产物。AIM 2将确定VPR与泛素连接酶复合体的相互作用如何影响HIV感染。具体目标3将集中于确定VPR介导的泛化靶标的身份，这对VPR介导的细胞周期停滞至关重要，并检查VPR参与促进泛化的复合体的正常功能。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The role of HIV-1 Vpr in promoting the infection of nondividing cells and in cell cycle arrest.

HIV-1 Vpr 在促进非分裂细胞感染和细胞周期停滞中的作用。

DOI：
10.1097/coh.0b013e32835049e0
发表时间：
2012
期刊：
Current opinion in HIV and AIDS
影响因子：
4.1
作者：
Sharifi,HamayunJ;Furuya,AndreaM;deNoronha,CarlosMC
通讯作者：
deNoronha,CarlosMC

The HIV1 protein Vpr acts to enhance constitutive DCAF1-dependent UNG2 turnover.

HIV1 蛋白 Vpr 的作用是增强 DCAF1 依赖性 UNG2 的组成型周转。

DOI：
10.1371/journal.pone.0030939
发表时间：
2012
期刊：
PloS one
影响因子：
3.7
作者：
Wen,Xiaoyun;CaseyKlockow,Laurieann;Nekorchuk,Michael;Sharifi,HamayunJ;deNoronha,CarlosMC
通讯作者：
deNoronha,CarlosMC

The HIV-1 protein Vpr targets the endoribonuclease Dicer for proteasomal degradation to boost macrophage infection.

DOI：
10.1016/j.virol.2013.06.010
发表时间：
2013-09
期刊：
Virology
影响因子：
3.7
作者：
Casey Klockow L;Sharifi HJ;Wen X;Flagg M;Furuya AK;Nekorchuk M;de Noronha CM
通讯作者：
de Noronha CM

HIV relies on neddylation for ubiquitin ligase-mediated functions.