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A Multidisciplinary Approach Defining the Functions and Regulation of the Antiviral Protein IFIX

机译：定义抗病毒蛋白IFIX的功能和调控的多学科方法

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摘要

A critical aspect of cellular defense is the intracellular recognition of foreign pathogens. Among these important defense factors are DNA sensors, proteins able to bind to foreign DNA and subsequently trigger immune responses. Recently, our lab identified a new viral DNA sensor, the interferon inducible protein IFIX. However, its mechanisms of action remained unknown. Therefore, for my PhD studies, I used an integrative approach that couple mass spectrometry-based proteomics with virology, molecular biology, and microscopy to characterize this important antiviral factor. I find that IFIX is capable of localizing to viral DNA both in the nucleus and cytoplasm of cells, in response to herpes simplex virus 1 (HSV-1) infection or vaccinia virus transfection, respectively. As IFIX is predominantly nuclear, I characterize the IFIX localization-dependent sensing by defining nuclear localization signals, and demonstrate its modulation by acetylation. Since the location of viral DNA is largely dependent on the type of virus and the host cell, these studies highlight the importance of mechanistic studies in understanding the regulation of early innate immune responses. To discover how IFIX exerts its antiviral functions, I focused on the human virus, HSV-1. By characterizing IFIX interactions with human and viral proteins during the progression of infection, I discovered potential antiviral functions. I establish that IFIX associates with proteins involved in transcriptional regulation. I demonstrate a dependency on IFIX in reducing HSV-1 viral progeny as well as viral gene transcription. Interestingly, I found that during infection with HSV-1, IFIX is targeted for proteasomal degradation. This indicates yet another host defense protein targeted by HSV-1 to combat host cell immune responses. Altogether, my studies define IFIX as a critical anti-viral factor against DNA viruses and highlight several mechanisms involved in its defense functions.
机译：细胞防御的一个关键方面是细胞内识别外来病原体。在这些重要的防御因素中，有DNA传感器，即能够与外源DNA结合并随后触发免疫反应的蛋白质。最近，我们的实验室确定了一种新的病毒DNA传感器，即干扰素诱导蛋白IFIX。但是，其作用机理仍然未知。因此，在我的博士研究中，我采用了一种整合方法，将基于质谱的蛋白质组学与病毒学，分子生物学和显微镜相结合，以表征这一重要的抗病毒因子。我发现IFIX能够分别响应单纯疱疹病毒1（HSV-1）感染或牛痘病毒转染而定位于细胞核和细胞质中的病毒DNA。由于IFIX主要是核的，因此我通过定义核定位信号来表征IFIX的局部依赖性传感，并通过乙酰化来证明其调节。由于病毒DNA的位置在很大程度上取决于病毒和宿主细胞的类型，因此这些研究强调了机理研究在理解早期先天免疫反应的调控中的重要性。为了发现IFIX如何发挥其抗病毒功能，我研究了人类病毒HSV-1。通过表征感染过程中IFIX与人和病毒蛋白的相互作用，我发现了潜在的抗病毒功能。我确定IFIX与参与转录调控的蛋白质缔合。我证明了在减少HSV-1病毒后代以及病毒基因转录方面对IFIX的依赖性。有趣的是，我发现在感染HSV-1期间，IFIX靶向蛋白酶体降解。这表明HSV-1靶向打击宿主细胞免疫反应的另一种宿主防御蛋白。总之，我的研究将IFIX定义为针对DNA病毒的关键抗病毒因子，并重点介绍了其防御功能涉及的几种机制。

著录项

  • 作者

    Crow, Marni Simone.;

  • 作者单位

    Princeton University.;

  • 授予单位 Princeton University.;
  • 学科 Molecular biology.
  • 学位 Ph.D.
  • 年度 2018
  • 页码 233 p.
  • 总页数 233
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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