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

• 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
• 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

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.

摘要： 疱疹病毒感染是一个主要的公共卫生问题。单纯疱疹病毒1型（HSV-1）是一种 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， 在人类的口腔和神经元感染中，HSV-1是感染引起的 人类的角膜炎和失明。建立感染和逃避的关键组成部分， 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 战略布局CD 1d限制性先天样NKT细胞对不同的抗微生物功能发挥关键作用 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 在感染和潜伏期期间避免了NKT细胞的有效抗微生物功能。我们有 发现HSV-1快速有效地下调抗原表面的CD 1d， 呈递细胞US 3是负责这种免疫逃避功能的主要病毒基因。通过 通过磷酸化，US 3激酶靶向主要的细胞运动蛋白KIF 3A，以抑制细胞内蛋白质的磷酸化。 逆行性胞内运输，介导CD 1d再循环至细胞表面。我们已经确定了三个 US 3激酶在KIF 3A中的新磷酸化位点。我们将描述每一个的分子功能 在抑制KIF 3A的折叠、组装和运动功能方面， 关闭KIF 3A介导转运并抑制CD 1d表面表达。成功结果 这一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， 并为关键马达蛋白KIF 3A及其功能机制提供了新的见解。 在免疫逃避中的重要性。