Modulation of cytokine-induced HIV gene expression by competitive binding of transcription factors to the coactivator p300.
The host response to viral infection involves the secretion of multiple cytokines which alter immune function and viral replication. These proteins activate several signal transduction pathways in infected cells which must be integrated to regulate cellular and viral gene expression. In this report, we demonstrate that specific transcription factors induced by distinct cytokines regulate HIV transcription by competitive binding to the p300 coactivator. Interferon-alpha (IFN-alpha) was found to inhibit NF-kappaB-dependent HIV gene expression stimulated by tumor necrosis factor-alpha (TNF-alpha). This inhibition was mediated by binding of the IFN-alpha signal transducer and activator of transcription 2, Stat2, to a specific domain of p300 which also binds to the RelA (p65) subunit of NF-kappaB. p300 was found to be limiting with respect to RelA (p65) and Stat2, and this effect was reversed by overexpression of p300. Inhibition by Stat2 was specific for NF-kappaB and was not mediated by Stat1, which is also induced by IFN-alpha. Gene activation induced by the Stat2 transcription domain was also inhibited by expression of RelA. These results demonstrate that HIV transcription can be regulated in the nucleus by competitive binding of specific cytokine-induced transcription factors to a discrete domain of a transcriptional coactivator.
Hottiger
M O
MO
Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor, MI 48109-0650, USA.
Felzien
L K
LK
Nabel
G J
GJ
D001667:Binding, Competitive / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D016207:Cytokines / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D006678:HIV / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D019169:Jurkat Cells; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000187:drug effects / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics; D017434:Protein Structure, Tertiary; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology; D051996:Transcription Factor RelA; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D016207:Cytokines; D004268:DNA-Binding Proteins; D016898:Interferon-alpha; D016328:NF-kappa B; D009687:Nuclear Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050795:STAT2 Transcription Factor; C494084:STAT2 protein, human; D015534:Trans-Activators; D051996:Transcription Factor RelA; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma