title: Zinc-finger antiviral protein inhibits HIV-1 infection by selectively targeting multiply spliced viral mRNAs for degradation.
abstract: The zinc-finger antiviral protein (ZAP) was originally identified as a host factor that inhibits the replication of Moloney murine leukemia virus. Here we report that ZAP inhibits HIV-1 infection by promoting the degradation of specific viral mRNAs. Overexpression of ZAP rendered cells resistant to HIV-1 infection in a ZAP expression level-dependent manner, whereas depletion of endogenous ZAP enhanced HIV-1 infection. Both human and rat ZAP inhibited the propagation of replication-competent HIV-1. ZAP specifically targeted the multiply spliced but not unspliced or singly spliced HIV-1 mRNAs for degradation. We provide evidence indicating that ZAP selectively recruits cellular poly(A)-specific ribonuclease (PARN) to shorten the poly(A) tail of target viral mRNA and recruits the RNA exosome to degrade the RNA body from the 3' end. In addition, ZAP recruits cellular decapping complex through its cofactor RNA helicase p72 to initiate degradation of the target viral mRNA from the 5' end. Depletion of each of these mRNA degradation enzymes reduced ZAP's activity. Our results indicate that ZAP inhibits HIV-1 by recruiting both the 5' and 3' mRNA degradation machinery to specifically promote the degradation of multiply spliced HIV-1 mRNAs.
authors.affiliation: Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Yiping
authors.initials: Y
authors.lastname: Zhu
authors.forename: Guifang
authors.initials: G
authors.lastname: Chen
authors.forename: Fengxiang
authors.initials: F
authors.lastname: Lv
authors.forename: Xinlu
authors.initials: X
authors.lastname: Wang
authors.forename: Xin
authors.initials: X
authors.lastname: Ji
authors.forename: Yihui
authors.initials: Y
authors.lastname: Xu
authors.forename: Jing
authors.initials: J
authors.lastname: Sun
authors.forename: Li
authors.initials: L
authors.lastname: Wu
authors.forename: Yong-Tang
authors.initials: YT
authors.lastname: Zheng
authors.forename: Guangxia
authors.initials: G
authors.lastname: Gao
mesh_terms: D017398:Alternative Splicing; D015153:Blotting, Western; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism; D005095:Exoribonucleases / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D015497:HIV-1 / Q000235:genetics* / Q000502:physiology; D054884:Host-Pathogen Interactions; D006801:Humans; D047468:Immunoprecipitation; D011485:Protein Binding; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism
chemical_list: D004722:Endoribonucleases; D005095:Exoribonucleases; D012333:RNA, Messenger; D012367:RNA, Viral; D016601:RNA-Binding Proteins; D015534:Trans-Activators; C527496:ZC3HAV1 protein, human; C466279:DCP1A protein, human; C467723:DCP2 protein, human