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: 8602832
• 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 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8602832
• 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）：病毒具有有限数量的基因，但具有复杂的生命周期。因此，它们已经进化到利用许多宿主因子来完成它们的复制。在HIV-1组装过程中，不同的病毒蛋白同步移动到质膜上的特定位点，从而实现病毒粒子的形态发生。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运输的后期。这些蛋白催化囊泡和靶室中相邻膜的对接和融合。SNAREs不仅参与胞内和胞外转运途径，还参与其他膜融合和裂变事件。其中包括细胞质分裂期间的子细胞分离，这一现象与HIV-1出芽的过程有着惊人的相似性。通过广泛破坏SNARE分选机制，我们最近证明了这些蛋白质通过影响Gag在质膜上的定位在HIV-1组装中的作用。初步数据表明，SNARE蛋白可能调节Gag与质膜结合/运输所需的细胞运输途径。在这项研究中，我们提出确定SNARE破坏影响HIV颗粒产生的精确机制。我们的目标是研究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破坏是否会影响细胞膜结构的完整性。最后，我们建议研究是否有特异性的“v”（囊泡相关）或“t”（靶膜相关）SNARE蛋白优先参与这一过程。这不仅将确定新的宿主因子在HIV生命周期中的作用，而且对病毒组装和释放途径的更好理解将有助于开辟新的抗病毒靶点的途径。