title: The HIV-1 Nef protein binds argonaute-2 and functions as a viral suppressor of RNA interference.
abstract: The HIV-1 accessory protein Nef is an important virulence factor. It associates with cellular membranes and modulates the endocytic machinery and signaling pathways. Nef also increases the proliferation of multivesicular bodies (MVBs), which are sites for virus assembly and budding in macrophages. The RNA interference (RNAi) pathway proteins Ago2 and GW182 localize to MVBs, suggesting these to be sites for assembly and turnover of the miRNA-induced silencing complex (miRISC). While RNAi affects HIV replication, it is not clear if the virus encodes a suppressor activity to overcome this innate host response. Here we show that Nef colocalizes with MVBs and binds Ago2 through two highly conserved Glycine-Tryptophan (GW) motifs, mutations in which abolish Nef binding to Ago2 and reduce virus yield and infectivity. Nef also inhibits the slicing activity of Ago2 and disturbs the sorting of GW182 into exosomes resulting in the suppression of miRNA-induced silencing. Thus, besides its other activities, the HIV-1 Nef protein is also proposed to function as a viral suppressor of RNAi (VSR).
authors.affiliation: International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi, India.
authors.forename: Madeeha
authors.initials: M
authors.lastname: Aqil
authors.forename: Afsar Raza
authors.initials: AR
authors.lastname: Naqvi
authors.forename: Aalia Shahr
authors.initials: AS
authors.lastname: Bano
authors.forename: Shahid
authors.initials: S
authors.lastname: Jameel
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D060565:Argonaute Proteins / Q000235:genetics / Q000378:metabolism*; D001324:Autoantigens / Q000378:metabolism; D002460:Cell Line; D017124:Conserved Sequence; D055354:Exosomes / Q000378:metabolism; D015497:HIV-1 / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D035683:MicroRNAs / Q000235:genetics; D008969:Molecular Sequence Data; D057146:Multivesicular Bodies / Q000378:metabolism; D009154:Mutation; D011485:Protein Binding; D021381:Protein Transport; D034622:RNA Interference; D012326:RNA Splicing; D016601:RNA-Binding Proteins / Q000378:metabolism; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000378:metabolism*
chemical_list: C466422:AGO2 protein, human; D060565:Argonaute Proteins; D001324:Autoantigens; D035683:MicroRNAs; D016601:RNA-Binding Proteins; C465663:TNRC6A protein, human; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1
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