Unraveling the molecular link between HIVAIDS and cancer

揭示艾滋病毒和癌症之间的分子联系

• 批准号: 10487135
• 负责人: Kyung Lee
• 金额: $ 22.43万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10487135
• 关键词: 2019-nCoV; ACE2; AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Address; Affinity; Aneuploidy; Animal Model; Binding; Biochemical; Biological; Biological Assay; C-terminal; COVID-19; COVID-19 pandemic; Cell Cycle; Cell Surface Receptors; Cell model; Cell physiology; Cells; Centrioles; Centrosome; Complex; Cultured Cells; Data; Development; Electron Microscopy; Etiology; Event; Genome Stability; Goals; HIV; HIV-1; HIV-2; Human; Immune system; Incidence; Infection; Intervention; Investigation; Lead; Light; Link; Lipid Bilayers; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Membrane Proteins; Molecular; Nature; Organelles; PLK1 gene; Pathogenesis; Persons; Phosphotransferases; Physiological; Process; Proteins; Proteomics; Research; Research Priority; Risk; Role; SARS-CoV-2 spike protein; Scaffolding Protein; Specificity; Structure; Tissues; United States National Institutes of Health; Viral; WD Repeat; X-Ray Crystallography; base; cancer risk; carcinogenesis; cellular targeting; chromosome missegregation; comorbidity; cryogenics; design; experience; extracellular; high risk; novel strategies; receptor; scaffold; small molecular inhibitor; small molecule inhibitor

Our unbiased proteomic mass spectrometry and subsequent biochemical analyses showed that Plk4 binds to the C-terminal acidic domain (1401-1507) of a cellular scaffold protein, VprBP, via its C-terminal cryptic polo-box. Strikingly, HIV-1 Vpr, which binds to the WD40 domain (1003-1400) of VprBP, greatly enhanced the VprBP-Plk4 interaction and induced the formation of the Vpr-VprBP-Plk4 complex. All three proteins colocalized to centrosomes and the formation of the ternary complex appeared to augment Plk4-mediated centriole duplication. Consistent with these findings, VprBP promoted Plk4 function by stabilizing its centriole-associated state rather than inducing its proteasomal degradation, as was observed for the Vpx-VprBP-SAMHD1 complex and other cellular targets. These data suggest that, when cells are infected with HIV-1, Vpr may alter Plk4's function by forming the Vpr-VprBP-Plk4 complex under physiological conditions and induce Plk4-dependent centriole overduplication, a cellular event causing aneuploidy and cancer. A structurally related HIV-2 Vpx failed to interact with VprBP and Plk4, indicating the specificity of HIV-1 Vpr-induced events. Based on these observations, we postulate that HIV-1 Vpr can directly alter genomic stability and facilitate carcinogenesis by hijacking the cellular Plk4-VprBP complex. Additional studies are planned to determine the role of the ternary Vpr-VprBP-Plk4 complex under physiologically relevant conditions, using HIV-1-susceptible cells and tissues in animal models. This research could shed light on the mechanism that could directly link HIV/AIDS to the etiology of its comorbid cancers. Furthermore, it may offer a new paradigm in understanding the increased cancer risk in people living with HIV-1. Investigating HIV-induced comorbidities is one of the four designated NIH HIV/AIDS research priorities. This research is designed to directly address HIV-1-associated cancer comorbidities. We have gained an enriched experience in studying how HIV proteins interact with cellular targets and alter cell physiology using various biochemical and structure-based analyses. Investigation into the way in which SARS-CoV-2 (COVID-19) recognizes its human cell surface receptor and isolation of small molecular inhibitors that disrupt this event would be critical for the intervention of viral entry into host cells. The exceptional high-affinity interaction between the COVID-19 spike protein (S protein) and the human extracellular receptor, ACE2, underlies the widespread pandemic of COVID-19. We are seeking to establish a specific COVID-19 S protein-ACE2 interaction trap using a membrane protein-friendly lipid-bilayer platform to isolate and develop small molecule inhibitors against COVID-19 entry into host cells.

我们无偏的蛋白质组学质谱法和随后的生化分析表明，PLK4通过其C-末端隐性Polo-box结合了细胞支架蛋白VPRBP的C末端酸性结构域（1401-1507）。令人惊讶的是，与VPRBP的WD40域（1003-1400）结合的HIV-1 VPR极大地增强了VPRBP-PLK4相互作用，并诱导了VPR-VPRBP-PLK4复合物的形成。所有三种蛋白质共定位于中心体，三元复合物的形成似乎增强了PLK4介导的中心复制。与这些发现一致，VPRBP通过稳定其中心相关状态而不是诱导其蛋白酶体降解来促进PLK4功能，正如VPX-VPRBP-SAMHD1复合物和其他细胞靶标所观察到的那样。这些数据表明，当细胞感染HIV-1时，VPR可能会通过在生理条件下形成VPR-VPRBP-PLK4复合物来改变PLK4的功能，并诱导PLK4依赖性中心二极管过度提取，从而导致肾上腺素和癌症。与结构相关的HIV-2 VPX未能与VPRBP和PLK4相互作用，表明HIV-1 VPR诱导的事件的特异性。基于这些观察结果，我们假设HIV-1 VPR可以通过劫持细胞PLK4-VPRBP复合物来直接改变基因组稳定性并促进癌变。计划在生理相关条件下使用HIV-1敏感细胞和动物模型中的组织在生理相关条件下确定三元VPR-VPRBP-PLK4复合物在生理相关条件下的作用。这项研究可以阐明可以将艾滋病毒/艾滋病与合并症癌症的病因联系起来的机制。此外，它可能为了解HIV-1患者的癌症风险增加而提供新的范式。研究HIV引起的合并症是四个指定的NIH HIV/AIDS研究重点之一。这项研究旨在直接解决与HIV-1相关的癌症合并症。我们在研究HIV蛋白如何与细胞靶标相互作用并使用各种基于生化和结构的分析改变细胞生理方面的经验丰富了经验。研究SARS-COV-2（COVID-19）识别其人类细胞表面受体的方式以及破坏此事件的小分子抑制剂的分离对于病毒进入宿主细胞的干预至关重要。 COVID-19-SPIKE蛋白（S蛋白）与人类外细胞受体ACE2之间的特殊高亲和力相互作用是Covid-19的广泛流行。我们正在寻求使用膜蛋白友好的脂质 - 双层平台建立特定的Covid-19s蛋白-ACE2相互作用陷阱，以隔离和开发小分子抑制剂，以防止与COVID-19进入宿主细胞的进入。