Regulation of T cell activation by HIV-1 accessory proteins: Vpr acts via distinct mechanisms to cooperate with Nef in NFAT-directed gene expression and to promote transactivation by CREB.
Nef and Vpr are lentiviral accessory proteins that have been implicated in regulation of cellular gene expression. We noticed that Vpr can potentiate Nef-induced activation of nuclear factor of activated T cells (NFAT)-dependent transcription. Unlike Nef, which stimulated calcium signaling to activate NFAT, Vpr functioned farther downstream. Similar to the positive effects of Vpr on most of the transcriptional test systems that we used, potentiation of NFAT-directed gene expression was relatively modest in magnitude (two- to threefold) and depended on the cell cycle-arresting capacity of Vpr. By contrast, we found that Vpr could cause more than fivefold upregulation of cyclic AMP response element (CRE)-directed transcription via a mechanism that did not require Vpr-induced G2/M arrest. This effect, however, was only evident under suboptimal conditions known to lead to serine phosphorylation of the CRE binding factor (CREB) but not to CREB-dependent gene expression. This suggested that Vpr may act by stabilizing interactions with CREB and its transcriptional cofactor CREB binding protein (CBP). Indeed, this effect could be blocked by cotransfection of the adenoviral CBP inhibitor E1A. These results provide additional evidence for cell cycle-independent regulation of gene expression by Vpr and implicate CREB as a potentially important target for Vpr action in HIV-infected host cells.
Lahti
Anna L
AL
Institute of Medical Technology, FIN-33014 University of Tampere, Tampere, Finland.
Manninen
Aki
A
Saksela
Kalle
K
D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000502:physiology*; D015967:Gene Expression Regulation, Viral; D015693:Gene Products, nef / Q000502:physiology*; D016336:Gene Products, vpr / Q000502:physiology*; D016325:HIV Long Terminal Repeat; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D015534:Trans-Activators / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology*; D015533:Transcriptional Activation; D054311:nef Gene Products, Human Immunodeficiency Virus; D054325:vpr Gene Products, Human Immunodeficiency Virus
D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D015693:Gene Products, nef; D016336:Gene Products, vpr; D050778:NFATC Transcription Factors; C494008:NFATC3 protein, human; C494010:NFATC4 protein, human; D009687:Nuclear Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D054311:nef Gene Products, Human Immunodeficiency Virus; D054325:vpr Gene Products, Human Immunodeficiency Virus; D013755:Tetradecanoylphorbol Acetate