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

I型干扰素（ifn）对抗病毒免疫至关重要，经常参与自身免疫病理。然而，ifn诱导和ifn介导的信号传导的调控尚不清楚。我们和其他人之前已经证明了各种去泛素化酶（DUBs），包括USP18， USP25和USP13，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反应和神经炎症。此外，我们已经确定USP15参与ifn信号传导和诱导。我们现在已经建立了一个新的Usp15fl/fl小鼠模型，在整个生物体的背景下探索其生理功能和分子机制。本提案的重点将是分析USP15在(i)中的作用。抗病毒免疫反应和(2)自身免疫性炎症性疾病。为了解决这一问题，本研究对缺乏USP15或经过诱导和细胞特异性消耗的小鼠进行了病毒感染，并对炎症模型DSS诱导的结肠炎和实验性自身免疫性脑炎（EAE）进行了挑战，并与对照动物进行了比较。我们将研究USP15在促炎信号通路、底物、蛋白质组组成和基因表达方面的分子作用。对小鼠模型和分子机制的分析将辅以对人类患者样本的检查，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，而且有可能将USP15定义为治疗干扰素病变、病毒感染和/或炎症性疾病的新药物靶点。

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.