Role of SNARE proteins in HIV-1 assembly and release

SNARE 蛋白在 HIV-1 组装和释放中的作用

• 批准号: 8466113
• 负责人: Anjali Joshi
• 金额: $ 7.55万
• 依托单位: TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8466113
• 关键词: ADP-Ribosylation Factors; Adaptor Signaling Protein; Affect; Architecture; Binding; Binding Proteins; Biological Assay; Biology; Carrier Proteins; Cell Separation; Cell membrane; Cell physiology; Cells; Cellular Membrane; Complex; Cytokinesis; Data; Defect; Docking; Ear; Employee Strikes; Ensure; Essential Genes; Event; Excision; Gagging; Genes; Golgi Apparatus; HIV; HIV Budding; HIV-1; Individual; Integration Host Factors; Life; Life Cycle Stages; Lipids; Mediating; Mediator of activation protein; Membrane; Membrane Fusion; Membrane Lipids; Membrane Microdomains; Mind; Morphogenesis; Movement; Organism; Pathway interactions; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositols; Play; Process; Production; Proteins; Role; SNAP receptor; Site; Sorting - Cell Movement; Staging; Structure; Ursidae Family; Vesicle; Viral; Viral Proteins; Virion; Virus; Virus Assembly; Virus-like particle; anterograde transport; base; daughter cell; drug discovery; extracellular; gag Gene Products; novel; particle; pathogen; public health relevance; receptor; retrograde transport; target SNARE proteins; trafficking

DESCRIPTION (provided by applicant): Viruses have a limited number of genes but a complex life cycle. They have hence evolved to utilize numerous host factors to complete their replication. With regard to HIV-1 assembly, a synchronized movement of different viral proteins to specific sites on the plasma membrane enables virion morphogenesis. The host SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins are widely involved in late stages of vesicular mediated transport. These proteins catalyze the docking and fusion of apposing membranes in the vesicle and target compartment. The SNAREs are involved not only in the endocytic and exocytic trafficking pathways but also in other membrane fusion and fission events. These include daughter cell separation during cytokinesis, a phenomenon that bears striking similarity to the process of HIV-1 budding. By generalized disruption of the SNARE sorting machinery, we recently demonstrated a role for these proteins in HIV-1 assembly by affecting Gag localization to the plasma membrane. Preliminary data suggests that SNARE proteins may regulate the cellular trafficking pathways required for Gag association/transport with the plasma membrane. In this study, we propose to define the precise mechanism via which SNARE disruption affects HIV particle production. We aim to study the effects of SNARE disruption on the cellular proteins and lipid components important for HIV particle production. We will also determine if SNARE disruption affects the integrity of the cellular membrane architecture. Finally, we propose to study whether there is a preferential involvement of specific "v" (vesicle-associated) or "t" (target membrane-associated) SNARE proteins in this process. This will not only define a role for novel host factors in the HIV life ccle but a better understanding of the virus assembly and release pathway will help open avenues for identifying novel anti-viral targets.

描述（由申请人提供）：病毒的基因数量有限，但生命周期复杂。因此，它们已经进化到利用许多宿主因子来完成其复制。关于HIV-1组装，不同病毒蛋白质同步移动到质膜上的特定位点使得病毒粒子形态发生成为可能。宿主SNARE（可溶性N-乙基马来酰亚胺敏感因子附着蛋白受体）蛋白广泛参与囊泡介导的转运的晚期阶段。这些蛋白质催化囊泡和靶区室中的并置膜的对接和融合。SNARE不仅参与胞吞和胞吐运输途径，还参与其他膜融合和裂变事件。其中包括胞质分裂过程中的子细胞分离，这一现象与HIV-1出芽过程惊人相似。通过对SNARE分选机制的普遍破坏，我们最近证明了这些蛋白质通过影响Gag定位于质膜在HIV-1组装中的作用。初步数据表明，SNARE蛋白可能调节细胞运输途径所需的Gag协会/运输与质膜。在这项研究中，我们建议定义SNARE破坏影响HIV颗粒产生的确切机制。我们的目的是研究SNARE破坏对HIV颗粒产生重要的细胞蛋白质和脂质成分的影响。我们还将确定SNARE破坏是否影响细胞膜结构的完整性。最后，我们建议研究是否有一个特定的“v”（囊泡相关）或“t”（目标膜相关）陷阱蛋白在这个过程中的优先参与。这不仅将定义新的宿主因子在HIV生命周期中的作用，而且更好地理解病毒组装和释放途径将有助于为识别新的抗病毒靶点开辟途径。