MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China; Shanghai Veterinary Research Institute, Chinese Academic of Agricultural Sciences, Shanghai 200241, PR China.
Shanghai Veterinary Research Institute, Chinese Academic of Agricultural Sciences, Shanghai 200241, PR China.
Virology. 2018 Jan 15;514:230-239. doi: 10.1016/j.virol.2017.11.004. Epub 2017 Dec 15.
The neddylation pathway belongs post-translational modifications and plays important roles in regulating viral infection and replication. To address the relationship of influenza A virus with the neddylation modification pathway, we demonstrate that IAV infection in A549 cells can activate the neddylation modification pathway to increase virus growth and enhance the expression of pro-inflammatory cytokines to increase pathogenicity. The pre-treatment of Nedd8-activating enzyme subunit 1 (NAE1)-specific inhibitor, MLN4924, interferes with Nedd8 conjugation and NF-κB activity. MLN4924 exhibited pronounced antiviral activity against different subtypes of influenza A virus, including classical H1N1 (PR8), H9N2 subtype, and pandemic H1N1 2009 (pdmH1N1) viruses. Through the inhibition of the CRL/NF-κB pathway, MLN4924 could significantly suppress the expression levels of pro-inflammatory cytokines induced by IAVs. These findings suggest that MLN4924 can be developed as a novel antiviral therapy for influenza infection for anti-viral efficacy and anti-inflammation activity.
泛素化途径属于翻译后修饰，在调节病毒感染和复制方面发挥着重要作用。为了研究甲型流感病毒（IAV）与泛素化修饰途径的关系，我们证明了 IAV 在 A549 细胞中的感染可以激活泛素化修饰途径，从而促进病毒生长，并增强促炎细胞因子的表达，增加致病性。Nedd8 激活酶亚基 1（NAE1）特异性抑制剂 MLN4924 的预处理会干扰 Nedd8 缀合和 NF-κB 活性。MLN4924 对不同亚型的流感病毒（包括经典的 H1N1（PR8）、H9N2 亚型和大流行 H1N1 2009（pdmH1N1）病毒）均表现出显著的抗病毒活性。通过抑制 CRL/NF-κB 途径，MLN4924 可以显著抑制 IAV 诱导的促炎细胞因子的表达水平。这些发现表明，MLN4924 可作为一种新型抗流感病毒感染的抗病毒疗法，兼具抗病毒疗效和抗炎活性。
