Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 11490, Taiwan.
J Immunol. 2013 Sep 15;191(6):3328-36. doi: 10.4049/jimmunol.1300225. Epub 2013 Aug 12.
The IFN immune system comprises type I, II, and III IFNs, signals through the JAK-STAT pathway, and plays central roles in host defense against viral infection. Posttranslational modifications such as ubiquitination regulate diverse molecules in the IFN pathway. To search for the deubiquitinating enzymes (DUBs) involved in the antiviral activity of IFN, we used RNA interference screening to identify a human DUB, ubiquitin-specific protease (USP) 13, whose expression modulates the antiviral activity of IFN-α against dengue virus serotype 2 (DEN-2). The signaling events and anti-DEN-2 activities of IFN-α and IFN-γ were reduced in cells with USP13 knockdown but enhanced with USP13 overexpression. USP13 may regulate STAT1 protein because the protein level and stability of STAT1 were increased with USP13 overexpression. Furthermore, STAT1 ubiquitination was reduced in cells with USP13 overexpression and increased with USP13 knockdown regardless of with or without IFN-α treatment. Thus, USP13 positively regulates type I and type II IFN signaling by deubiquitinating and stabilizing STAT1 protein. Overall, to our knowledge, USP13 is the first DUB identified to modulate STAT1 and play a role in the antiviral activity of IFN against DEN-2 replication.
IFN 免疫系统包括 I 型、II 型和 III 型 IFN，通过 JAK-STAT 途径传递信号，在宿主防御病毒感染中发挥核心作用。翻译后修饰（如泛素化）调节 IFN 途径中的多种分子。为了寻找参与 IFN 抗病毒活性的去泛素化酶（DUB），我们使用 RNA 干扰筛选鉴定了一种人类 DUB，即泛素特异性蛋白酶（USP）13，其表达可调节 IFN-α 对登革热病毒血清型 2（DEN-2）的抗病毒活性。USP13 敲低的细胞中 IFN-α 和 IFN-γ 的信号事件和抗 DEN-2 活性降低，但 USP13 过表达的细胞中增强。USP13 可能调节 STAT1 蛋白，因为 STAT1 的蛋白水平和稳定性在 USP13 过表达时增加。此外，无论是否有 IFN-α 处理，USP13 过表达的细胞中 STAT1 泛素化减少，USP13 敲低的细胞中 STAT1 泛素化增加。因此，USP13 通过去泛素化和稳定 STAT1 蛋白正向调节 I 型和 II 型 IFN 信号。总的来说，据我们所知，USP13 是第一个被鉴定为调节 STAT1 并在 IFN 对抗 DEN-2 复制的抗病毒活性中发挥作用的 DUB。
