CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100101, China; Department of Virology, State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China; Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China; Suzhou Institute of System Medicine, Suzhou, Jiangsu 215123, China.
Institute for Immunity, Transplantation and Infection, Department of Pathology, Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA.
Cell Rep. 2020 Nov 3;33(5):108342. doi: 10.1016/j.celrep.2020.108342.
Influenza A virus (IAV) infection stimulates a type I interferon (IFN-I) response in host cells that exerts antiviral effects by inducing the expression of hundreds of IFN-stimulated genes (ISGs). However, most ISGs are poorly studied for their roles in the infection of IAV. Herein, we demonstrate that SERTA domain containing 3 (SERTAD3) has a significant inhibitory effect on IAV replication in vitro. More importantly, Sertad3 mice develop more severe symptoms upon IAV infection. Mechanistically, we find SERTAD3 reduces IAV replication through interacting with viral polymerase basic protein 2 (PB2), polymerase basic protein 1 (PB1), and polymerase acidic protein (PA) to disrupt the formation of the RNA-dependent RNA polymerase (RdRp) complex. We further identify an 8-amino-acid peptide of SERTAD3 as a minimum interacting motif that can disrupt RdRp complex formation and inhibit IAV replication. Thus, our studies not only identify SERTAD3 as an antiviral ISG, but also provide the mechanism of potential application of SERTAD3-derived peptide in suppressing influenza replication.
甲型流感病毒（IAV）感染可刺激宿主细胞中的 I 型干扰素（IFN-I）应答，通过诱导数百种干扰素刺激基因（ISGs）的表达来发挥抗病毒作用。然而，大多数 ISGs 在 IAV 感染中的作用仍未得到充分研究。在此，我们证明 SERTA 结构域包含 3（SERTAD3）在体外对 IAV 复制具有显著的抑制作用。更重要的是，Sertad3 小鼠在 IAV 感染后会出现更严重的症状。从机制上讲，我们发现 SERTAD3 通过与病毒聚合酶碱性蛋白 2（PB2）、聚合酶碱性蛋白 1（PB1）和聚合酶酸性蛋白（PA）相互作用来减少 IAV 复制，从而破坏 RNA 依赖性 RNA 聚合酶（RdRp）复合物的形成。我们进一步确定 SERTAD3 的一个 8 个氨基酸肽是一个最小的相互作用基序，可以破坏 RdRp 复合物的形成并抑制 IAV 复制。因此，我们的研究不仅确定了 SERTAD3 作为一种抗病毒 ISG，还为 SERTAD3 衍生肽在抑制流感病毒复制方面的潜在应用提供了机制。
