Analysis of the ISG15 conjugation and deconjugation system in vivo

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Protein modification by the Interferon Stimulated Gene 15 (ISG15) is mediated by the specific E1 activating enzyme Ube1L, the E2 ligase UbCH8 and HERC5 as the major human E3 ligase. ISGylation is counteracted by the cysteine protease UBP43 and reported to be involved in multiple biological processes like innate immunity, viral defence and the control of malignant proliferation. We identified mHERC6 as the major murine ISG15 E3 ligase and currently generate conditional knockout mice to analyze the function of this protein in vivo. To evaluate the role of ISG15 deconjugation we generated mice where the isopeptidase activity of UBP43 was specifically inactivated. As a consequence levels of ISGylation are enhanced, accompanied by higher resistance to viral infection. We will continue to analyze these mice to determine the role of ISG15 deconjugation and thus evaluate the potential for therapeutic inhibition of UBP43. To investigate molecular functions, new UBP43 interaction partners were identified and will be analyzed.