Analysis of the ISG15 conjugation and deconjugation system in vivo

ISG15 体内缀合和解缀系统分析

• 批准号: 71963973
• 负责人: Privatdozent Dr. Klaus-Peter Knobeloch
• 金额: --
• 依托单位: Institut für Neuropathologie
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2008
• 资助国家: 德国
• 起止时间: 2007-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/71963973?language=en
• 关键词: Analysis; ISG15; conjugation; deconjugation; system

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.

干扰素刺激基因15（ISG15）的蛋白质修饰由特异性E1激活酶Ube1L、E2连接酶UbCH 8和作为主要人E3连接酶的HERC5介导。ISG化被半胱氨酸蛋白酶UBP 43抵消，并且据报道参与多种生物过程，如先天免疫、病毒防御和恶性增殖的控制。我们将mHERC6鉴定为主要的鼠ISG15 E3连接酶，并且目前产生条件性敲除小鼠以分析该蛋白在体内的功能。为了评估ISG15去缀合的作用，我们产生了其中UBP 43的异肽酶活性被特异性灭活的小鼠。因此，ISG化水平提高，伴随着对病毒感染的更高抗性。我们将继续分析这些小鼠以确定ISG15去缀合的作用，从而评估UBP 43的治疗性抑制的潜力。为了研究分子功能，鉴定并分析了新的UBP 43相互作用伴侣。