MDM2 is a novel E3 ligase for HIV-1 Vif.
MDM2 is a novel E3 ligase for HIV-1 Vif.
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DOI：
10.1186/1742-4690-6-1
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发表时间：
2009-01-07
期刊：
影响因子：
3.3
通讯作者：
Uchiyama, Takashi
中科院分区：
文献类型：
--
作者：
Izumi, Taisuke;Takaori-Kondo, Akifumi;Shirakawa, Kotaro;Higashitsuji, Hiroaki;Itoh, Katsuhiko;Io, Katsuhiro;Matsui, Masashi;Iwai, Kazuhiro;Kondoh, Hiroshi;Sato, Toshihiro;Tomonaga, Mitsunori;Ikeda, Satoru;Akari, Hirofumi;Koyanagi, Yoshio;Fujita, Jun;Uchiyama, Takashi
人类免疫缺陷病毒1型（HIV-1）Vif通过拮抗宿主限制因子APOBEC 3G（A3 G）在病毒生命周期中起着至关重要的作用。Vif与A3 G相互作用，通过与Cullin 5-ElonginB/C形成活性泛素连接酶（E3）复合物，诱导其多聚泛素化和随后的降解。虽然Vif本身也被泛素化并在感染细胞中迅速降解，但Vif泛素化的确切作用和机制在很大程度上是未知的。在这里，我们报告MDM 2，被称为p53的E3连接酶，是Vif的一种新型E3连接酶，并诱导Vif的多聚泛素化和降解。我们还展示了MDM 2仅靶向Vif而不靶向与Vif结合的A3 G的机制。MDM 2降低了细胞Vif水平，而A3 G增加了A3 G水平，因为MDM 2和Vif之间的相互作用阻止了A3 G与Vif结合。此外，我们证明MDM 2通过Vif降解负调控非允许靶细胞中的HIV-1复制。这些数据表明MDM 2是HIV-1复制的调节因子，可能是抗HIV-1药物的新的治疗靶点。
The human immunodeficiency virus type 1 (HIV-1) Vif plays a crucial role in the viral life cycle by antagonizing a host restriction factor APOBEC3G (A3G). Vif interacts with A3G and induces its polyubiquitination and subsequent degradation via the formation of active ubiquitin ligase (E3) complex with Cullin5-ElonginB/C. Although Vif itself is also ubiquitinated and degraded rapidly in infected cells, precise roles and mechanisms of Vif ubiquitination are largely unknown. Here we report that MDM2, known as an E3 ligase for p53, is a novel E3 ligase for Vif and induces polyubiquitination and degradation of Vif. We also show the mechanisms by which MDM2 only targets Vif, but not A3G that binds to Vif. MDM2 reduces cellular Vif levels and reversely increases A3G levels, because the interaction between MDM2 and Vif precludes A3G from binding to Vif. Furthermore, we demonstrate that MDM2 negatively regulates HIV-1 replication in non-permissive target cells through Vif degradation. These data suggest that MDM2 is a regulator of HIV-1 replication and might be a novel therapeutic target for anti-HIV-1 drug.
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