Elucidating the molecular mechanism of intracellular DNA recognition by the innate immune sensor IFI16

阐明先天免疫传感器IFI16识别细胞内DNA的分子机制

• 批准号: MR/K00655X/2
• 负责人: Leonie Unterholzner
• 金额: $ 55.62万
• 依托单位: Lancaster University
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK00655X%2F2
• 关键词: Elucidating; molecular; mechanism; intracellular; DNA

In this project, we would like to investigate how the cells in our body can protect themselves by detecting 'stranger' and a 'danger' signals. As part of the innate immune system, most cells in our body notice when they have been infected by viruses or other 'strangers' by recognising tell-tale signs of infection, such as the presence of viral DNA. Once a virus has been detected, the cells respond immediately by releasing alarm signals, such as interferons. These then help to combat the virus locally and call specialised immune cells to the site of infection. Over the last decade an intensive research effort has lead to the discovery of several proteins that can sense signs of infection, called pathogen recognition receptors. We have recently identified a new receptor, IFI16, that can sense viral DNA inside cells, and protects the cell from infection with herpesviruses. In this project, we would like to investigate in more detail how this DNA receptor works, and how cells recognise different kinds of DNA.We will address three major questions:1.) Which other proteins co-operate with IFI16 in the recognition of viral DNA?2.) How can a cell distinguish between viral DNA and the cell's own DNA genome?3.) How is DNA sensed as a 'danger' as well as a 'stranger' signal?We will try and answer these questions by using isolated human cells grown in vitro. These cells can be infected with DNA viruses, and then the alarm responses can be measured. We will also use large-scale experimental approaches to find new players that help in the recognition of DNA. For instance, we are planning to use a high-throughput robotic platform to screen more than 20,000 genes of the human genome for their involvement in DNA sensing. While this is a basic research project not aimed at immediately providing new cures, it may nevertheless provide crucial knowledge that can help in combating disease in the future. For instance, knowing how the body recognises viral DNA may be important for the development of new vaccines. Also, the recognition of DNA as a 'danger' signal has important clinical implications. The body's own DNA can activate the innate immune system under some circumstances, for instance when broken up DNA from dead cells is not cleared effectively. This can then lead to the development of autoimmune diseases, where an excessive immune response attacks the body's own tissues. Knowing which pattern recognition receptors cause this response would provide potential targets for treatment, so that this unwanted immune response can be dampened. Another instance where DNA is recognised as a 'danger' signal is when DNA has been damaged by ultraviolet light or by toxic chemicals. In this case, the innate immune system may be alerted to the danger posed by these damaged cells, and eliminate them, in order to prevent the development of cancer. Studying how DNA is sensed in these various circumstances would provide crucial insights for the development of treatments that modulate the innate immune response.

在这个项目中，我们想研究我们体内的细胞如何通过检测“陌生人”和“危险”信号来保护自己。作为先天免疫系统的一部分，我们体内的大多数细胞通过识别感染的迹象（如病毒DNA的存在）来注意它们何时被病毒或其他“陌生人”感染。一旦检测到病毒，细胞会立即释放警报信号，如干扰素。然后，这些有助于在局部对抗病毒，并将专门的免疫细胞召集到感染部位。 在过去的十年里，一项密集的研究工作已经发现了几种可以感知感染迹象的蛋白质，称为病原体识别受体。我们最近发现了一种新的受体，IFI16，它可以感知细胞内的病毒DNA，并保护细胞免受疱疹病毒的感染。在这个项目中，我们想更详细地研究这种DNA受体是如何工作的，以及细胞如何识别不同类型的DNA。我们将解决三个主要问题：哪些其他蛋白质与IFI16合作识别病毒DNA？2.）的情况。细胞如何区分病毒DNA和细胞自身的DNA基因组？3.）第三章DNA是如何被感知为“危险”和“陌生人”信号的？我们将尝试通过使用体外培养的分离的人类细胞来回答这些问题。这些细胞可以被DNA病毒感染，然后可以测量警报反应。我们还将使用大规模的实验方法来寻找有助于识别DNA的新参与者。例如，我们计划使用高通量机器人平台来筛选人类基因组中参与DNA传感的20，000多个基因。虽然这是一个基础研究项目，目的不是立即提供新的治疗方法，但它可能提供有助于未来防治疾病的关键知识。例如，了解人体如何识别病毒DNA可能对新疫苗的开发很重要。此外，将DNA识别为“危险”信号具有重要的临床意义。在某些情况下，身体自身的DNA可以激活先天免疫系统，例如当死亡细胞的DNA不能有效清除时。这可能导致自身免疫性疾病的发展，其中过度的免疫反应攻击身体自身的组织。知道哪些模式识别受体引起这种反应将为治疗提供潜在的目标，从而可以抑制这种不必要的免疫反应。DNA被认为是“危险”信号的另一个例子是DNA被紫外线或有毒化学物质破坏。在这种情况下，先天免疫系统可能会对这些受损细胞构成的危险发出警报，并消除它们，以防止癌症的发展。研究DNA在这些不同的情况下是如何被感知的，将为开发调节先天免疫反应的治疗方法提供重要的见解。

项目成果

Structural mechanism of DNA recognition by the p204 HIN domain.

p204 HIN 结构域识别 DNA 的结构机制

• DOI: 10.1093/nar/gkab076
• 发表时间: 2021-03-18
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Fan X;Jiang J;Zhao D;Chen F;Ma H;Smith P;Unterholzner L;Xiao TS;Jin T
• 通讯作者: Jin T

IFI16 and cGAS cooperate in the activation of STING during DNA sensing in human keratinocytes.

• DOI: 10.1038/ncomms14392
• 发表时间: 2017-02-13
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Almine JF;O'Hare CA;Dunphy G;Haga IR;Naik RJ;Atrih A;Connolly DJ;Taylor J;Kelsall IR;Bowie AG;Beard PM;Unterholzner L
• 通讯作者: Unterholzner L