MDM2 is a novel E3 ligase for HIV-1 Vif

doi:10.1186/1742-4690-6-1

Retrovirology

Volume 6

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Izumi T
Takaori-Kondo A
Shirakawa K
Higashitsuji H
Itoh K
Io K
Matsui M
Iwai K
Kondoh H
Sato T
Tomonaga M
Ikeda S
Akari H
Koyanagi Y
Fujita J
Uchiyama T

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Izumi T
Takaori-Kondo A
Shirakawa K
Higashitsuji H
Itoh K
Io K
Matsui M
Iwai K
Kondoh H
Sato T
Tomonaga M
Ikeda S
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Uchiyama T
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Research

MDM2 is a novel E3 ligase for HIV-1 Vif

Taisuke Izumi¹ , Akifumi Takaori-Kondo¹ , Kotaro Shirakawa¹^,2 , Hiroaki Higashitsuji³ , Katsuhiko Itoh³ , Katsuhiro Io¹ , Masashi Matsui¹ , Kazuhiro Iwai⁴^,5 , Hiroshi Kondoh⁶ , Toshihiro Sato⁷ , Mitsunori Tomonaga⁷ , Satoru Ikeda⁷ , Hirofumi Akari⁸ , Yoshio Koyanagi⁹ , Jun Fujita³ and Takashi Uchiyama¹

¹Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawaracho, Sakyo-ku, Kyoto 606-8507, Japan

²Japanese Foundation for AIDS Prevention, 1-3-12 Misaki-cho, Chiyoda-ku, Tokyo 101-0061, Japan

³Department of Clinical Molecular Biology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawaracho, Sakyo-ku, Kyoto 606-8507, Japan

⁴Department of Molecular Cell Biology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan

⁵CREST, Japan Science Technology Corporation, Kawaguchi, Saitama 332-0012, Japan

⁶Department of Geriatric Medicine, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawaracho, Sakyo-ku, Kyoto 606-8507, Japan

⁷Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan

⁸Laboratory of Disease Control, Tukuba Primate Research Center, National Institute of Biomedical Innovation, Hachimandai-1, Tsukuba, Ibaraki 305-0843, Japan

⁹Laboratory of Viral Pathgenesis, Institute for Virus Research, Kyoto University, 53 Shogoin-Kawaracho, Sakyo-ku, Kyoto 606-8507, Japan

author email corresponding author email

Retrovirology 2009, 6:1doi:10.1186/1742-4690-6-1


Published:	7 January 2009

Abstract

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.