DataSheet_1_DNA-PKcs restricts Zika virus spreading and is required for effective antiviral response.pdf

Zika virus (ZIKV) is a single-strand RNA mosquito-borne flavivirus with significant public health impact. ZIKV infection induces double-strand DNA breaks (DSBs) in human neural progenitor cells that may contribute to severe neuronal manifestations in newborns. The DNA-PK complex plays a critical role in repairing DSBs and in the innate immune response to infection. It is unknown, however, whether DNA-PK regulates ZIKV infection. Here we investigated the role of DNA-PKcs, the catalytic subunit of DNA-PK, during ZIKV infection. We demonstrate that DNA-PKcs restricts the spread of ZIKV infection in human epithelial cells. Increased ZIKV replication and spread in DNA-PKcs deficient cells is related to a notable decrease in transcription of type I and III interferons as well as IFIT1, IFIT2, and IL6. This was shown to be independent of IRF1, IRF3, or p65, canonical transcription factors necessary for activation of both type I and III interferon promoters. The mechanism of DNA-PKcs to restrict ZIKV infection is independent of DSB. Thus, these data suggest a non-canonical role for DNA-PK during Zika virus infection, acting downstream of IFNs transcription factors for an efficient antiviral immune response.

寨卡病毒（ZIKV）是一种单链RNA蚊子传播的黄病毒，对公共卫生具有重大影响。寨卡病毒感染可导致人神经祖细胞中的双链DNA断裂（DSBs），这可能与新生儿严重的神经症状有关。DNA-PK复合体在修复DSBs和感染后的先天免疫反应中发挥着关键作用。然而，目前尚不清楚DNA-PK是否调节寨卡病毒的感染。在本研究中，我们调查了DNA-PKcs（DNA-PK的催化亚基）在寨卡病毒感染中的作用。我们证明DNA-PKcs限制了寨卡病毒在人类上皮细胞中的传播。DNA-PKcs缺陷细胞中寨卡病毒的复制和传播增加与I型和III型干扰素以及IFIT1、IFIT2和IL6转录的显著减少有关。这一现象被证明与IRF1、IRF3或p65等经典转录因子无关，这些转录因子对于激活I型和III型干扰素启动子是必需的。DNA-PKcs限制寨卡病毒感染的作用机制与DSBs无关。因此，这些数据表明，DNA-PK在寨卡病毒感染中发挥着非经典的作用，它在IFN转录因子下游发挥作用，以实现有效的抗病毒免疫反应。