Role of Optineurin in Ocular Herpes Infection

Optineurin 在眼部疱疹感染中的作用

• 批准号: 8430175
• 负责人: DEEPAK SHUKLA
• 金额: $ 23.93万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8430175
• 关键词: Adult; Amyotrophic Lateral Sclerosis; Animal Model; Antibodies; Area; Autophagocytosis; Binding; Biological Assay; Blindness; Brain; Cell fusion; Cell membrane; Cell surface; Cells; Cessation of life; Co-Immunoprecipitations; Complex; Cornea; Data; Degenerative Disorder; Diagnostic; Down-Regulation; Doxycycline; Epithelial Cells; Etiology; Exocytosis; Eye; Eye Infections; Future; Genes; Glaucoma; Glycoproteins; Golgi Apparatus; Growth; Herpesvirus 1; Herpetic Keratitis; Human; Immunofluorescence Immunologic; Infection; Infection Control; Integration Host Factors; Interferons; Investigation; Joints; Laboratories; Life; Link; Lytic Phase; Movement; Mus; Phosphorylation; Play; Process; Production; Protein Biosynthesis; Proteins; RNA Interference; RNA Viruses; Regulation; Reporting; Resolution; Role; Secretory Vesicles; Surface; TANK-binding kinase 1; Testing; Tetanus Helper Peptide; Time; Tissues; Vaccines; Vesicle; Viral; Viral Interference; Viral Proteins; Virus; Virus Diseases; adapter protein; base; cell type; cellular imaging; cofactor; corneal epithelium; inhibition of autophagy; mutant; myosin VI; novel; overexpression; protein transport; public health relevance; response

DESCRIPTION (provided by applicant): Herpes simplex virus type-1 (HSV-1) can cause irreversible damage to the human cornea and is capable of infecting virtually all major cell types in the eye. The virus is also considered a cofactor in causation of secondary glaucoma and is thought to play similar roles in certain degenerative diseases of the human brain. A lytic infection by HSV-1 is known to down regulate host protein synthesis to favor viral protein production. Very limited information is available on the host proteins that are up-regulated during the infection. This proposal is focused on understanding the function(s) of a cellular protein, optineurin (OPTN), an autophagy adapter protein, in HSV-1 infection of the eye. The gene encoding OPTN has been implicated in glaucoma and amyotrophic lateral sclerosis. Our preliminary data shows that OPTN is widely expressed in human and murine corneas. We have also found that OPTN is up-regulated in response to HSV-1 infection of human corneal epithelial (HCE) cells and transient over-expression of OPTN in HCE cells results in an increased number of plaques formed by HSV-1. This exploratory proposal will test the hypothesis that OPTN is a key to a productive infection of the human corneal cells by HSV-1. We propose to explore two independent roles for OPTN in HSV-1 infection. The first Aim will focus on the possibility that HSV-1 infection interferes with OPTN phosphorylation by TANK binding kinase-1 (TBK1), which in turn results in the inhibition of autophagy induction and interferon production, and viral replication ensues. The second Aim will examine a role for OPTN, via interaction with myosin VI, in the transport of newly made HSV-1 glycoproteins and fusion of virus-laden vesicles with the plasma membrane that facilitate the virus release from cells. Overall, our studies are expected to shed new lights, and for the first time, implicate OPTN as an important co-factor in HSV-1 infection of the cells in the cornea.

描述（由申请人提供）：1 型单纯疱疹病毒 (HSV-1) 可对人类角膜造成不可逆的损伤，并且能够感染眼睛中几乎所有主要细胞类型。该病毒也被认为是导致继发性青光眼的辅助因子，并且被认为在人类大脑的某些退行性疾病中发挥类似的作用。众所周知，HSV-1 的裂解性感染会下调宿主蛋白质合成，从而有利于病毒蛋白质的产生。关于感染期间上调的宿主蛋白的信息非常有限。该提案的重点是了解细胞蛋白 optineurin (OPTN)（一种自噬衔接蛋白）在眼睛 HSV-1 感染中的功能。编码 OPTN 的基因与青光眼和肌萎缩侧索硬化症有关。我们的初步数据显示 OPTN 在人类和小鼠角膜中广泛表达。我们还发现，OPTN 在人角膜上皮 (HCE) 细胞的 HSV-1 感染反应中上调，并且 HCE 细胞中 OPTN 的瞬时过度表达导致 HSV-1 形成的斑块数量增加。该探索性提案将检验以下假设：OPTN 是 HSV-1 有效感染人类角膜细胞的关键。我们建议探索 OPTN 在 HSV-1 感染中的两个独立作用。第一个目标将关注 HSV-1 感染通过 TANK 结合激酶 1 (TBK1) 干扰 OPTN 磷酸化的可能性，从而抑制自噬诱导和干扰素产生，并随之发生病毒复制。第二个目标将通过与肌球蛋白 VI 相互作用，研究 OPTN 在新制造的 HSV-1 糖蛋白的运输以及载有病毒的囊泡与质膜的融合（促进病毒从细胞中释放）中的作用。总体而言，我们的研究有望揭示新的线索，并首次表明 OPTN 是角膜细胞 HSV-1 感染的重要辅助因子。