title: ASK1 restores the antiviral activity of APOBEC3G by disrupting HIV-1 Vif-mediated counteraction.
abstract: 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.
authors.affiliation: Department of Microbiology, Yokohama City University School of Medicine, Kanagawa 236-0004, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Miyakawa
authors.affiliation: Department of Microbiology, Yokohama City University School of Medicine, Kanagawa 236-0004, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Matsunaga
authors.affiliation: Infectious Disease Surveillance Center, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Kanou
authors.affiliation: Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Matsuzawa
authors.affiliation: 1] Department of Microbiology, Yokohama City University School of Medicine, Kanagawa 236-0004, Japan [2] CellFree Sciences Co. Ltd., Ehime University Venture, Ehime 790-8577, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Morishita
authors.affiliation: Department of Microbiology, Yokohama City University School of Medicine, Kanagawa 236-0004, Japan.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Kudoh
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Shindo
authors.affiliation: Pathogen Genomics Center, National Institute of Infectious Diseases, Tokyo 208-0011, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Yokoyama
authors.affiliation: Pathogen Genomics Center, National Institute of Infectious Diseases, Tokyo 208-0011, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Sato
authors.affiliation: Infectious Disease Surveillance Center, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Kimura
authors.affiliation: Department of Immunology, Yokohama City University School of Medicine, Kanagawa 236-0004, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Tamura
authors.affiliation: Department of Microbiology, National University of Singapore, Singapore 117597, Singapore.
authors.forename: Naoki
authors.initials: N
authors.lastname: Yamamoto
authors.affiliation: Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ichijo
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Akifumi
authors.identifier: 0000000176784284
authors.initials: A
authors.lastname: Takaori-Kondo
authors.affiliation: Department of Microbiology, Yokohama City University School of Medicine, Kanagawa 236-0004, Japan.
authors.forename: Akihide
authors.initials: A
authors.lastname: Ryo
mesh_terms: D000071480:APOBEC-3G Deaminase; D019380:Anti-HIV Agents / Q000494:pharmacology; D003564:Cytidine Deaminase / Q000187:drug effects / Q000378:metabolism*; D057809:HEK293 Cells; D015497:HIV-1 / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D048848:MAP Kinase Kinase Kinase 5 / Q000187:drug effects / Q000378:metabolism*; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism*; D054875:Ubiquitination; D014771:Virion / Q000187:drug effects / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects; D015215:Zidovudine / Q000494:pharmacology; D054320:vif Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: D019380:Anti-HIV Agents; D054320:vif Gene Products, Human Immunodeficiency Virus; C514847:vif protein, Human immunodeficiency virus 1; D015215:Zidovudine; D043743:Ubiquitin-Protein Ligase Complexes; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human; D000071480:APOBEC-3G Deaminase; C464924:APOBEC3G protein, human; D003564:Cytidine Deaminase