Department of Infectious Diseases, School of Immunology and Microbial Sciences, King's College London, London, United Kingdom.
MRC Laboratory for Molecular Cell Biology, University College London, London, United Kingdom.
Elife. 2019 Jul 9;8:e46767. doi: 10.7554/eLife.46767.
CpG dinucleotides are suppressed in most vertebrate RNA viruses, including HIV-1, and introducing CpGs into RNA virus genomes inhibits their replication. The zinc finger antiviral protein (ZAP) binds regions of viral RNA containing CpGs and targets them for degradation. ZAP does not have enzymatic activity and recruits other cellular proteins to inhibit viral replication. We found that KHNYN, a protein with no previously known function, interacts with ZAP. KHNYN overexpression selectively inhibits HIV-1 containing clustered CpG dinucleotides and this requires ZAP and its cofactor TRIM25. KHNYN requires both its KH-like domain and NYN endonuclease domain for antiviral activity. Crucially, depletion of KHNYN eliminated the deleterious effect of CpG dinucleotides on HIV-1 RNA abundance and infectious virus production and also enhanced the production of murine leukemia virus. Overall, we have identified KHNYN as a novel cofactor for ZAP to target CpG-containing retroviral RNA for degradation.
CpG 二核苷酸在大多数脊椎动物 RNA 病毒中受到抑制，包括 HIV-1，将 CpG 引入 RNA 病毒基因组会抑制其复制。锌指抗病毒蛋白 (ZAP) 结合含有 CpG 的病毒 RNA 区域，并将其靶向降解。ZAP 没有酶活性，它招募其他细胞蛋白来抑制病毒复制。我们发现，KHNYN 是一种具有未知功能的蛋白质，与 ZAP 相互作用。KHNYN 的过表达选择性地抑制含有簇状 CpG 二核苷酸的 HIV-1，这需要 ZAP 和其辅助因子 TRIM25。KHNYN 的 KH 样结构域和 NYN 内切酶结构域都需要其发挥抗病毒活性。至关重要的是，KHNYN 的耗竭消除了 CpG 二核苷酸对 HIV-1 RNA 丰度和感染性病毒产生的有害影响，同时也增强了鼠白血病病毒的产生。总的来说，我们已经确定 KHNYN 是 ZAP 的一种新型辅助因子，可靶向含有 CpG 的逆转录病毒 RNA 进行降解。
