title: Inhibition of ER stress-mediated apoptosis in macrophages by nuclear-cytoplasmic relocalization of eEF1A by the HIV-1 Nef protein.
abstract: HIV-1 Nef protein has key roles at almost all stages of the viral life cycle. We assessed the role of the Nef/eEF1A (eukaryotic translation elongation factor 1-alpha) complex in nucleocytoplasmic shuttling in primary human macrophages. Nuclear retention experiments and inhibition of the exportin-t (Exp-t) pathway suggested that cytoplasmic relocalization of eEF1A, mediated by Exp-t, occurs in Nef-treated monocyte-derived macrophages (MDMs). We observed the presence of tRNA in the Nef/eEF1A complexes. Nucleocytoplasmic relocalization of the Nef/eEF1A complexes prevented stress-induced apoptosis of MDMs treated with brefeldin-A. Blockade of stress-induced apoptosis of MDMs treated with HIV-1 Nef resulted from enhanced nucleocytoplasmic transport of eEF1A with decreased release of mitochondrial cytochrome c, and from increased tRNA binding to cytochrome c, ultimately leading to an inhibition of caspase activation. Our results indicate that HIV-1 Nef, through the nucleocytoplasmic relocalization of eEF1A and tRNAs, enhances resistance to stress-induced apoptosis in primary human macrophages.
authors.affiliation: Department of Virology, University of Franche-Comte, EA 4266, INSERM IFR 133, CHU Besancon, Besançon F-25030, France.
authors.forename: W
authors.initials: W
authors.lastname: Abbas
authors.forename: K A
authors.initials: KA
authors.lastname: Khan
authors.forename: M K
authors.initials: MK
authors.lastname: Tripathy
authors.forename: I
authors.initials: I
authors.lastname: Dichamp
authors.forename: M
authors.initials: M
authors.lastname: Keita
authors.forename: O
authors.initials: O
authors.lastname: Rohr
authors.forename: G
authors.initials: G
authors.lastname: Herbein
mesh_terms: D021581:Active Transport, Cell Nucleus; D017209:Apoptosis / Q000187:drug effects*; D020126:Brefeldin A / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D015497:HIV-1 / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D029543:Nucleocytoplasmic Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020648:Peptide Elongation Factor 1 / Q000378:metabolism*; D011485:Protein Binding; D025941:Protein Interaction Mapping; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D012343:RNA, Transfer / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*
chemical_list: C094814:EEF1A1 protein, human; D029543:Nucleocytoplasmic Transport Proteins; D020648:Peptide Elongation Factor 1; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; C503618:XPOT protein, human; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1; D020126:Brefeldin A; D045304:Cytochromes c; D012343:RNA, Transfer; D053148:Caspase 3; D053453:Caspase 9