Regulation of antiviral immunity and autoimmune inflammation by the deubiquitinating enzyme USP15

I型干扰素（IFN）是抗病毒免疫所必需的，并且经常参与自身免疫病理学。然而，IFN-诱导和IFN-介导的信号转导的调节还没有很好地理解。我们和其他人先前已经证明，包括USP 18、USP 25和USP 13在内的各种去泛素化酶（DUB）通过调节IFN诱导和/或IFN触发的信号传导来调节抗病毒免疫应答和神经炎症。此外，我们已经确定USP 15参与IFN信号传导和诱导。我们现在已经产生了一种新的Usp 15 fl/fl小鼠模型，以探索整个生物体背景下的生理功能和分子机制。本提案的重点将是分析USP 15在（I.）抗病毒免疫应答和（II.）自身免疫炎性疾病。为了解决这一问题，组成型缺乏USP 15或在诱导和细胞特异性消耗后的小鼠将被病毒感染以及通过DSS诱导的结肠炎和实验性自身免疫性脑炎（EAE）的炎症模型攻击，并与对照动物进行比较。将研究USP 15对促炎信号通路、底物、蛋白质组组成和基因表达的影响的分子作用。对小鼠模型和分子机制的分析将通过对人类患者样本的检查来补充，以确定与炎症性疾病的潜在相关性和/或功能关系。我们相信，这项研究不仅将促进我们对免疫和炎症反应的理解，而且还具有将USP 15定义为治疗干扰素病，病毒感染和/或炎症性疾病的新型药物靶点的潜力。

Type I interferons (IFNs) are essential for antiviral immunity and often involved in autoimmune pathology. However, the regulation of IFN-induction and IFN-mediated signaling is not well understood. We and others have previously demonstrated that various deubiquitinating enzymes (DUBs) including USP18, USP25, and USP13 regulate antiviral immune responses and neuroinflammation through modulating IFN-induction and/or IFN-triggered signaling. In addition, we have identified USP15 being involved in IFN-signaling and induction. We have now generated a novel Usp15fl/fl mouse model to explore the physiological functions and the molecular mechanisms within the context of the whole organism. The focus of this proposal will be to analyze the role of USP15 in (I.) Antiviral immune responses and (II.) Autoimmune inflammatory diseases. To address this, mice either constitutively lacking USP15 or upon induced and cell-specific depletion will be virally infected as well as challenged by the inflammation models DSS induced colitis and experimental autoimmune encephalitis (EAE) and examined in comparison to control animals. The molecular role(s) of USP15 will be investigated with respect to the influence on pro-inflammatory signaling pathways, substrates, proteome composition and gene expression. Analysis of mouse models and molecular mechanisms will be complemented by the examination of samples from human patients to identify potential correlations and/or functional relationships with inflammatory diseases. We believe that this study will not only advance our understanding of immune and inflammatory responses, but also harbors the potential to define USP15 as a novel drug target for the treatment of interferonopathies, viral infections and/or inflammatory diseases.