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

• Applicant: Privatdozent Dr. Klaus-Peter Knobeloch
• Subject Area: Immunology
• Term: from 2018 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 407678805

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.

• DFG Programme: Research Grants
• International Connection: China
• Cooperation Partner: Professor Dr. Bo Zhong