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: 10926459
• 负责人: Kyung Lee
• 金额: $ 51.83万
• 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/10926459
• 关键词: Acidic Region; Acquired Immunodeficiency Syndrome; Address; Aneuploidy; Animal Model; Binding; Biochemical; Biological; Biological Assay; Blood; C-terminal; CD4 Positive T Lymphocytes; Cell Cycle; Cell model; Cell physiology; Cells; Centrioles; Centrosome; Complex; Cryoelectron Microscopy; Cultured Cells; Data; Development; Disease; Etiology; Event; Genome Stability; Goals; HIV; HIV-1; HIV-2; HIV/AIDS; Human; Immune system; Incidence; Infection; Investigation; Light; Link; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Molecular; Nature; Organelles; PLK1 gene; Pathogenesis; Persons; Phosphotransferases; Physiological; Predisposition; Process; Proteins; Proteomics; Research; Research Priority; Risk; Role; Scaffolding Protein; Shapes; Specificity; Structure; T-Lymphocyte; Tail; Tissues; United States National Institutes of Health; WD Repeat; Work; X-Ray Crystallography; antiretroviral therapy; cancer risk; carcinogenesis; cellular targeting; chromosome missegregation; comorbidity; design; experience; high risk; inhibitor; interest; novel strategies; prevent; scaffold; tumorigenesis

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 ternary complex formation 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 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. Furthermore, our efforts to determine the quaternary structure of the Vpr-VprBP-Plk4 complex have been moving along well. Once the quaternary structure is determined, we will be interested in designing inhibitors that could disrupt the complex and thus help prevent HIV-1-induced centrosomal abnormalities and their associated human disorders, such as cancer. The data that we obtained from various cultured cells revealed that disrupting the Vpr-VprBP-Plk4 complex by either deleting the Vpr's C-terminal tail or the VprBP's acidic region was sufficient to abolish Vpr-dependent centrosome amplification and aneuploidy in multiple CD4+ cells, including primary T cells. Given the tight association of aneuploidy and cancer, these findings suggest that the HIV-1-induced Vpr-VprBP-Plk4 complex can directly promote oncogenesis in HIV-1-susceptible T cells or other blood Vpr-transducible cells by hijacking the host machinery for Plk4-mediated centriole duplication. In light of the finding that the risk of developing NHL remains high even during the combination antiretroviral therapy, this work may offer a new direction for investigating underlying mechanisms that give rise to HIV-1-associated cancers.

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依赖性中心二元过度提取，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。计划进行其他研究，以确定使用HIV-1敏感细胞和动物模型中的HIV-1敏感细胞和组织在生理相关条件下三元VPR-VPRBP-PLK4复合物的作用。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。此外，我们为确定VPR-VPRBP-PLK4配合物的第四纪结构的努力一直很好地移动。一旦确定了第四纪结构，我们将有兴趣设计可能破坏复合物的抑制剂，从而有助于预防HIV-1诱导的中心体异常及其相关的人类疾病，例如癌症。我们从各种培养的细胞中获得的数据表明，通过删除VPR的C末端尾巴或VPRBP的酸性区域来破坏VPR-VPRBP-PLK4复合物，足以消除多个CD4+细胞（包括一级T细胞）中的依赖VPR的中心体扩增和肾上腺素。鉴于非整倍性和癌症的紧密关联，这些发现表明，HIV-1诱导的VPR-VPRBP-PLK4复合物可以直接促进HIV-1敏感的T细胞中的HIV-1敏感性T细胞或其他血液VPR变性细胞，通过劫持PLK4介导的Centriole centriole centriole centriole重复现式。鉴于发现即使在抗逆转录病毒疗法中，发展NHL的风险仍然很高，这项工作可能为研究引起HIV-1相关癌症的基本机制提供了新的方向。