Le-Trilling Vu Thuy Khanh, Megger Dominik A, Katschinski Benjamin, Landsberg Christine D, Rückborn Meike U, Tao Sha, Krawczyk Adalbert, Bayer Wibke, Drexler Ingo, Tenbusch Matthias, Sitek Barbara, Trilling Mirko
Institute for Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
Medizinisches Proteom-Center, Ruhr Universität Bochum, Bochum, Germany.
Sci Rep. 2016 Feb 1;6:19977. doi: 10.1038/srep19977.
In terms of infected human individuals, herpesviruses range among the most successful virus families. Subclinical herpesviral infections in healthy individuals contrast with life-threatening syndromes under immunocompromising and immunoimmature conditions. Based on our finding that cytomegaloviruses interact with Cullin Roc ubiquitin ligases (CRLs) in the context of interferon antagonism, we systematically assessed viral dependency on CRLs by utilizing the drug MLN4924. CRL activity is regulated through the conjugation of Cullins with the ubiquitin-like molecule Nedd8. By inhibiting the Nedd8-activating Enzyme (NAE), MLN4924 interferes with Nedd8 conjugation and CRL activity. MLN4924 exhibited pronounced antiviral activity against mouse and human cytomegalovirus, herpes simplex virus (HSV)- 1 (including multi-drug resistant clinical isolates), HSV-2, adeno and influenza viruses. Human cytomegalovirus genome amplification was blocked at nanomolar MLN4924 concentrations. Global proteome analyses revealed that MLN4924 blocks cytomegaloviral replication despite increased IE1 amounts. Expression of dominant negative Cullins assigned this IE regulation to defined Cullin molecules and phenocopied the antiviral effect of MLN4924.
就受感染的人类个体而言，疱疹病毒是最成功的病毒家族之一。健康个体中的亚临床疱疹病毒感染与免疫功能低下和免疫未成熟条件下的危及生命的综合征形成对比。基于我们发现巨细胞病毒在干扰素拮抗的背景下与Cullin Roc泛素连接酶（CRL）相互作用，我们通过使用药物MLN4924系统地评估了病毒对CRL的依赖性。CRL活性通过Cullins与类泛素分子Nedd8的结合来调节。通过抑制Nedd8激活酶（NAE），MLN4924干扰Nedd8结合和CRL活性。MLN4924对小鼠和人类巨细胞病毒、单纯疱疹病毒（HSV）-1（包括多重耐药临床分离株）、HSV-2、腺病毒和流感病毒表现出显著的抗病毒活性。在纳摩尔浓度的MLN4924下，人类巨细胞病毒基因组扩增被阻断。全球蛋白质组分析表明，尽管IE1量增加，MLN4924仍能阻断巨细胞病毒的复制。显性负性Cullins的表达将这种IE调节归因于特定的Cullin分子，并模拟了MLN4924的抗病毒作用。
