Suppression of KIF3A function by herpes simplex virus-1 US3 kinase for immune evasion

单纯疱疹病毒1 US3激酶抑制KIF3A功能以逃避免疫

基本信息

批准号：
10082431
负责人：
Weiming Yuan
金额：
$ 20.63万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-08 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10082431
关键词：
Adaptive Immune System Address Antigen Presentation Antigen-Presenting Cells Antigens Antiviral Therapy Bacteria Binding Blindness C-terminal CD1d antigen Cell physiology Cell surface Cells Coiled-Coil Domain Cytotoxic T-Lymphocytes Disease Down-Regulation Encephalitis Etiology Event Family Fractionation Genes Glycolipids Goals Herpesviridae Herpesviridae Infections Herpesvirus 1 Human Immune Immune Evasion Immune response Immune system Individual Infection Keratitis Kinesin Lead Life Ligands MHC Class I Genes Malignant Neoplasms Mediating Membrane Molecular Molecular Conformation Morbidity - disease rate Motor N-terminal Natural Immunity Natural Killer Cells Neurons Oral Outcome Parasites Pathogenesis Phosphorylation Phosphorylation Site Phosphotransferases Play Procedures Proteins Public Health Recycling Role Simplexvirus Surface Surface Antigens Surveys System Therapeutic Vaccine Design Viral Genes Virus Virus Diseases antimicrobial antiviral immunity base cytokine fungus innovation insight latent infection member mortality novel pathogen prototype retrograde transport therapy design trafficking

项目摘要

Abstract: Herpesvirus infection is a major public health problem. Herpes Simplex virus-1 (HSV-1) is the prototype member of alpha-herpesvirus family. In additional to causing high morbidity and mortality in oral and neuronal infection in humans, HSV-1 is the leading etiological agent for infection-caused ocular keratitis and blindness for humans. To establish infection and escape critical components of the immune systems to remain latent in host cells, HSV-1 has evolved sophisticated immune evasion strategies. CD1d-restricted innate-like NKT cells play critical anti-microbial functions against different pathogens, including viruses, bacteria, fungi, and parasites. However, it remains unclear how HSV-1 evades the potent anti-microbial functions of NKT cells during infection and latency. We have discovered that HSV-1 rapidly and efficiently down-regulates CD1d from the surface of antigen- presenting cells. US3 is the primary viral gene responsible for this immune evasion function. Through phosphorylation, the US3 kinase targets the major cellular motor protein, KIF3A to inhibit the retrograde endosmal trafficking that mediates CD1d recycling to cell surface. We have identified three new phosphorylation sites in KIF3A by US3 kinase. We will delineate the molecular function of each phosphorylation event in suppressing the folding, assembly, and motor function of KIF3A to rapidly shut down KIF3A-mediated transport and inhibit CD1d surface expression. Successful outcome of this proposal will significantly impact our understanding of herpesvirus-mediated immune evasion as well as provides novel insights for functional mechanism of key motor protein KIF3A and its importance in immune evasion of CD1d.

抽象的：疱疹病毒感染是一个重大的公共卫生问题。单纯疱疹病毒 1 (HSV-1) 是 α-疱疹病毒家族的原型成员。除了造成高发病率和死亡率外人类口腔和神经元感染，HSV-1 是引起感染的主要病原体人类眼部角膜炎和失明。建立感染并逃脱关键组件免疫系统在宿主细胞中保持潜伏状态，HSV-1 已经进化出复杂的免疫逃避策略。 CD1d 限制的先天性 NKT 细胞针对不同的细菌发挥关键的抗微生物功能病原体，包括病毒、细菌、真菌和寄生虫。然而，目前尚不清楚HSV-1如何在感染和潜伏期逃避 NKT 细胞的强大抗微生物功能。我们有发现HSV-1快速有效地下调抗原表面的CD1d- 呈现细胞。 US3 是负责这种免疫逃避功能的主要病毒基因。通过磷酸化后，US3 激酶靶向主要细胞运动蛋白 KIF3A，以抑制介导 CD1d 再循环至细胞表面的逆行内质运输。我们已经确定了三个 US3 激酶在 KIF3A 中新的磷酸化位点。我们将描述每个分子的功能磷酸化事件抑制 KIF3A 的折叠、组装和运动功能以快速关闭 KIF3A 介导的运输并抑制 CD1d 表面表达。成功的结果该提议将极大地影响我们对疱疹病毒介导的免疫逃避的理解并为关键运动蛋白 KIF3A 及其功能机制提供了新的见解 CD1d 在免疫逃避中的重要性。