IFI27 inhibits HIV-1 replication by degrading Gag protein through the ubiquitin-proteasome pathway

作者：Wenqiang He, Wei Pang, Na Li, Anqi Li, Yihui Li, Ying Lu, Fan Shen, Rong Xin, Tian‐Zhang Song, Ren‐Rong Tian, Liu-Meng Yang, Yong‐Tang Zheng · 发表于：Journal of Virology · 年份：2024 · DOI：10.1128/jvi.01356-24 · 被引用次数：9 · 研究领域：HIV Research and Treatment、interferon and immune responses、Cytomegalovirus and herpesvirus research

ABSTRACT Type I interferon (IFN-I) and its downstream genes play a profound role in HIV infection. In this study, we found that an IFN-inducible gene, IFI27, was upregulated in HIV-1 infection, which in turn efficiently suppressed HIV-1 replication, specially degraded the viral gag protein, including p24 and p55 subunits. Notably, the anti-HIV-1 activity of IFI27 in Old World monkeys surpassed that in New World monkeys, and IFI27 has a higher potentially inhibitory effect on HIV-1 than simian immunodeficiency virus (SIV). Our initial observations showed that NPM-IFI27, the IFI27 variant in northern pig-tailed macaque ( Macaca leonina , NPM), exhibited a strong anti-HIV-1 activity. Further investigation demonstrated that NPM-IFI27 degraded p24 and p55 via the ubiquitin-proteasome pathway, with NPM-IFI27-37–115 interacting with the p24-N domain, and the NPM-IFI27-76–122 domain was closely associated with K48 ubiquitin recruitment. Additionally, Skp2 was identified as the probable E3 ubiquitin ligase responsible for the degradation of p24 and p55. Similarly, human IFI27 (Hu-IFI27) showed a mechanism similar to NPM-IFI27 in HIV-1 inhibition. These findings underscore the pivotal role of NPM-IFI27 in HIV-1 infection and provide a potential strategy for clinical anti-HIV-1 therapy. IMPORTANCE HIV-1 infection can trigger the production of IFN-I, which subsequently activates the expression of various IFN-stimulated genes (ISGs) to antagonize the virus. Therefore, discovering novel ho...