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

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(HSV-1)是 阿尔法疱疹病毒家族的原型成员。除了造成高发病率和死亡率外， 人类口腔和神经感染中，HSV-1是感染引起的主要病原体 人类的眼角膜炎和失明。确定感染并逃脱关键组件 免疫系统在宿主细胞中保持潜伏，HSV-1进化出复杂的免疫逃避 战略。CD1d受限的先天类NKT细胞对不同的 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是如何 在感染和潜伏期间逃避NKT细胞强大的抗微生物功能。我们有 发现HSV-1快速而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。穿过 磷酸化，US3激酶以主要的细胞运动蛋白KIF3A为靶点，抑制 介导CD1d循环到细胞表面的逆行内膜运输。我们已经确认了三个 US3激酶在KIF3A中发现新的磷酸化位点。我们将描述每个分子的功能 快速抑制KIF3A折叠、组装和运动功能中的磷酸化事件 关闭KIF3A介导的转运，抑制CD1d的表面表达。成功的结果 这一提议将显著影响我们对疱疹病毒介导的免疫逃避的理解，因为 为关键的运动蛋白KIF3A及其受体的作用机制提供了新的见解 CD1d在免疫逃避中的重要性。

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.