Mechanisms of Virus Entry into Cells and Antiviral Barriers Limiting Entry

病毒进入细胞的机制和限制进入的抗病毒屏障

基本信息

批准号：
10926320
负责人：
Alex Compton
金额：
$ 84.78万
依托单位：
DIVISION OF BASIC SCIENCES - NCI
依托单位国家：
美国
项目类别：
财政年份：
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/10926320
关键词：
2019-nCoV Affect Amphipathic Alpha Helix Antiviral Therapy Binding Cell membrane Cell physiology Cells Cellular Membrane Cellular Structures Cholesterol Development Ensure Exhibits Glean HIV-1 Half-Life Human IFITM1 gene Immune response Immunologic Factors Immunology Influenza A virus Integral Membrane Protein Interferons Journals Learning Lipid Binding Membrane Membrane Fusion Membrane Microdomains Molecular Molecular Biology Nature Play Population Printing Process Protein Family Proteins Publishing Receptor Signaling Reporting Role Therapeutic Intervention Viral Viral Physiology Virus Work Zika Virus biophysical properties gene therapy human pathogen in silico insight molecular dynamics new therapeutic target novel pathogenic virus receptor response scaffold therapeutic target trafficking tumorigenesis tumorigenic tyrosine receptor viral transmission

项目摘要

We published two articles pertaining to this project in 2020 (Ahi et al., mBio, 2020; Rahman et al., eLife 2020), two articles in 2022 (Rahman et al., Journal of Molecular Biology, 2022; Majdoul et al., Nature Reviews Immunology, 2022), and one preprint so far in 2023 (Shi et al., bioRxiv, 2023). Our work provides extensive insight into the function of IFITM proteins as well as the extended CD225 protein family to which they belong and will provide leverage for the development of new antiviral therapies. Notably, we identified an amphipathic alpha helix that is required for the antiviral activity of IFITM3 against multiple viruses, including HIV-1, Zika virus, and Influenza A virus (Chesarino, Compton et al. EMBO Reports, 2017). Subsequently, we showed that the amphipathic helix is required for the ability of IFITM3 to alter the biophysical properties of cellular membranes (membrane rigidity and curvature) (Rahman et al., eLife, 2020). Most recently, we demonstrated that the amphipathic helix exhibits direct cholesterol binding activity, providing a possible explanation for its impacts on membranes and a plausible mechanism for how IFITM3 restricts membrane fusion pore formation (Rahman et al., Journal of Molecular Biology, 2022). We now plan to examine how cholesterol binding by IFITM3 directly contributes to its antiviral activities by incorporating in silico analyses using molecular dynamics simulations. We will also assess how lipid binding by IFITM3 affects its trafficking through the cell and protein half-life. In addition, our findings will allow us to better understand the cellular roles played by IFITM3 and related proteins, including its ability to act as a scaffold for receptor tyrosine receptor signaling at lipid rafts in the plasma membrane. Our findings will provide insight into the poorly characterized tumorigenic roles played by this family of proteins and provide therapeutic targets for inactivation.

我们在 2020 年发表了两篇与该项目相关的文章（Ahi et al., mBio, 2020；Rahman et al., eLife 2020），在 2022 年发表了两篇文章（Rahman et al., Journal of Molecular Biology, 2022；Majdoul et al., 2022）。，《自然评论免疫学》，2022 年），以及 2023 年迄今为止的一份预印本（Shi 等人， BioRxiv，2023）。我们的工作对 IFITM 蛋白及其所属的扩展 CD225 蛋白家族的功能提供了广泛的了解，并将为新的抗病毒疗法的开发提供杠杆作用。值得注意的是，我们发现了 IFITM3 针对多种病毒（包括 HIV-1、寨卡病毒和甲型流感病毒）的抗病毒活性所需的两亲性 α 螺旋（Chesarino、Compton 等人 EMBO 报告，2017）。随后，我们证明了 IFITM3 改变细胞膜生物物理特性（膜刚性和曲率）的能力需要两亲螺旋（Rahman 等人，eLife，2020）。最近，我们证明两亲性螺旋表现出直接的胆固醇结合活性，为其对膜的影响提供了可能的解释，并为 IFITM3 如何限制膜融合孔形成提供了合理的机制（Rahman 等人，分子生物学杂志，2022）。我们现在计划通过分子动力学模拟纳入计算机分析，研究 IFITM3 与胆固醇的结合如何直接促进其抗病毒活性。我们还将评估 IFITM3 的脂质结合如何影响其在细胞中的运输和蛋白质半衰期。此外，我们的研究结果将使我们能够更好地了解 IFITM3 和相关蛋白所发挥的细胞作用，包括其作为质膜脂筏上受体酪氨酸受体信号传导支架的能力。我们的研究结果将深入了解该蛋白质家族所发挥的尚未明确的致瘤作用，并提供失活的治疗靶点。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

More than meets the I: the diverse antiviral and cellular functions of interferon-induced transmembrane proteins.

DOI：
10.1186/s12977-017-0377-y
发表时间：
2017-11-21
期刊：
Retrovirology
影响因子：
3.3
作者：
Shi G;Schwartz O;Compton AA
通讯作者：
Compton AA

Cholesterol Binds the Amphipathic Helix of IFITM3 and Regulates Antiviral Activity.

DOI：
10.1016/j.jmb.2022.167759
发表时间：
2022-10-15
期刊：
JOURNAL OF MOLECULAR BIOLOGY
影响因子：
5.6
作者：
Rahman, Kazi;Datta, Siddhartha A. K.;Beaven, Andrew H.;Jolley, Abigail A.;Sodt, Alexander J.;Compton, Alex A.
通讯作者：
Compton, Alex A.

Homology-guided identification of a conserved motif linking the antiviral functions of IFITM3 to its oligomeric state.