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A novel role of HSP70 proteins in antiviral immune response

HSP70 蛋白在抗病毒免疫反应中的新作用

基本信息

批准号：
346764907
负责人：
Professor Dr. Karl-Klaus Conzelmann
金额：
--
依托单位：
Genzentrum - Laboratorium für molekulare Biologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2017
资助国家：
德国
起止时间：
2016-12-31 至 2021-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/346764907?language=en
关键词：
novel role HSP70 proteins antiviral

项目摘要

Transcriptional induction of type I and III interferons (IFN) in response to non-self or atypical self-nucleic acids is a crucial step in the activation of antiviral innate immunity and inflammation, and a process that needs to be tightly controlled, as excessive and chronic IFN induction may lead to autoimmune diseases. In our previous work we have identified a so far not appreciated crucial role of the cellular HSP70 protein family in regulation of RIG-I like receptor-mediated IFN induction. Initially, HSP70 was identified as a direct target of the rabies virus phosphoprotein P, a potent IFN antagonist. Direct binding of P to HSP70 is mediated by a specific P peptide motif, and distinct from HSP70 substrate binding. Binding to HSP70 strictly correlates with the ability of P to shut down activation of the IFN transcription factor IRF3, as shown by mutagenesis of plasmid-expressed P and engineered recombinant viruses. Expression of selected HSP70 mutants strongly interferes with IFN induction by RIG-I, further confirming an intrinsic regulatory role in the control of IFN induction. In the present project we aim at specifying the novel role of heat shock and possibly multiple HSP70 members in regulation of the IFN response, and to clarify how viral proteins like P can exploit HSPs to prevent the antiviral host response. The studies involve mutational and pharmacological analyses of the pleiotropic HSP70 functions, and cell biological studies in the absence and presence of engineered P proteins. The results might allow devising novel strategies for antiviral treatment or immune suppression.

响应于非自身或非典型自身核酸的I型和III型干扰素（IFN）的转录诱导是抗病毒先天免疫和炎症激活中的关键步骤，并且是需要严格控制的过程，因为过度和慢性IFN诱导可能导致自身免疫性疾病。在我们以前的工作中，我们已经确定了一个迄今为止尚未认识到的关键作用的细胞HSP 70蛋白家族在调节RIG-I样受体介导的IFN诱导。最初，HSP 70被鉴定为狂犬病病毒磷蛋白P（一种有效的IFN拮抗剂）的直接靶点。P与HSP 70的直接结合由特异性P肽基序介导，并且不同于HSP 70底物结合。与HSP 70的结合与P关闭IFN转录因子IRF 3的激活的能力严格相关，如质粒表达的P和工程重组病毒的诱变所示。所选HSP 70突变体的表达强烈干扰RIG-I的IFN诱导，进一步证实了IFN诱导控制中的内在调节作用。在本项目中，我们的目标是指定热休克和可能的多个HSP 70成员在IFN反应的调节中的新作用，并澄清病毒蛋白如P如何利用HSPs来防止抗病毒宿主反应。这些研究涉及多效性HSP 70功能的突变和药理学分析，以及在缺乏和存在工程P蛋白的情况下的细胞生物学研究。这些结果可能有助于设计新的抗病毒治疗或免疫抑制策略。