Miyakawa Kei, Matsunaga Satoko, Kanou Kazuhiko, Matsuzawa Atsushi, Morishita Ryo, Kudoh Ayumi, Shindo Keisuke, Yokoyama Masaru, Sato Hironori, Kimura Hirokazu, Tamura Tomohiko, Yamamoto Naoki, Ichijo Hidenori, Takaori-Kondo Akifumi, Ryo Akihide
Department of Microbiology, Yokohama City University School of Medicine, Kanagawa 236-0004, Japan.
Infectious Disease Surveillance Center, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.
Nat Commun. 2015 Apr 22;6:6945. doi: 10.1038/ncomms7945.
APOBEC3G (A3G) is an innate antiviral restriction factor that strongly inhibits the replication of human immunodeficiency virus type 1 (HIV-1). An HIV-1 accessory protein, Vif, hijacks the host ubiquitin-proteasome system to execute A3G degradation. Identification of the host pathways that obstruct the action of Vif could provide a new strategy for blocking viral replication. We demonstrate here that the host protein ASK1 (apoptosis signal-regulating kinase 1) interferes with the counteraction by Vif and revitalizes A3G-mediated viral restriction. ASK1 binds the BC-box of Vif, thereby disrupting the assembly of the Vif-ubiquitin ligase complex. Consequently, ASK1 stabilizes A3G and promotes its incorporation into viral particles, ultimately reducing viral infectivity. Furthermore, treatment with the antiretroviral drug AZT (zidovudine) induces ASK1 expression and restores the antiviral activity of A3G in HIV-1-infected cells. This study thus demonstrates a distinct function of ASK1 in restoring the host antiviral system that can be enhanced by AZT treatment.
载脂蛋白B mRNA编辑酶催化多肽样蛋白3G（APOBEC3G，A3G）是一种先天性抗病毒限制因子，可强烈抑制1型人类免疫缺陷病毒（HIV-1）的复制。HIV-1辅助蛋白Vif会利用宿主泛素-蛋白酶体系统来促使A3G降解。鉴定阻碍Vif作用的宿主途径可为阻断病毒复制提供新策略。我们在此证明，宿主蛋白凋亡信号调节激酶1（ASK1）会干扰Vif的拮抗作用，并恢复A3G介导的病毒限制作用。ASK1与Vif的BC盒结合，从而破坏Vif-泛素连接酶复合物的组装。因此，ASK1可稳定A3G并促进其掺入病毒颗粒，最终降低病毒感染力。此外，抗逆转录病毒药物齐多夫定（AZT）处理可诱导ASK1表达，并恢复A3G在HIV-1感染细胞中的抗病毒活性。因此，本研究证明了ASK1在恢复宿主抗病毒系统方面的独特功能，而AZT处理可增强这一功能。
