Negative Regulation of HIV-1 Transcription by a Heterodimeric NF-κB1/p50 and C-Terminally Truncated STAT5 Complex

Signal transducers and activator of transcription (STAT) proteins are often constitutively activated in leukocytes of HIV-1 + individuals, which frequently show a dominant expression of a C-terminally truncated isoform of STAT5 (STAT5Δ) . STAT5Δ can act as a negative regulator of human immunodeficie...

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Bibliographic Details
Published in:Journal of molecular biology 2011-07, Vol.410 (5), p.933-943
Main Authors: Della Chiara, Giulia, Crotti, Andrea, Liboi, Elio, Giacca, Mauro, Poli, Guido, Lusic, Marina
Format: Article
Language:English
Subjects:
binding sites
Blood
CD8 antigen
Cell Nucleus - drug effects
Cell Nucleus - metabolism
Chromatin
Chromatin Immunoprecipitation
DNA-directed RNA polymerase
Granulocyte-macrophage colony-stimulating factor
Granulocyte-Macrophage Colony-Stimulating Factor - pharmacology
HIV Infections - metabolism
HIV Long Terminal Repeat - genetics
HIV-1
HIV-1 - drug effects
HIV-1 - genetics
Human immunodeficiency virus 1
Humans
Immunoprecipitation
latency
leukocytes
Long terminal repeat
LTR
Monocytes
Mutant Proteins - metabolism
NF- Kappa B protein
NF-kappa B p50 Subunit - metabolism
p50 NF-κB
Phosphorylation
precipitin tests
Promoter Regions, Genetic
Promoters
Protein Binding - drug effects
Protein Multimerization - drug effects
RelA protein
Sequence Deletion - genetics
Stat protein
STAT5
Stat5 protein
STAT5 Transcription Factor - metabolism
Subcellular Fractions - drug effects
Subcellular Fractions - metabolism
terminal repeat sequences
Transcription
transcription factor NF-kappa B
Transcription, Genetic - drug effects
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Summary:Signal transducers and activator of transcription (STAT) proteins are often constitutively activated in leukocytes of HIV-1 + individuals, which frequently show a dominant expression of a C-terminally truncated isoform of STAT5 (STAT5Δ) . STAT5Δ can act as a negative regulator of human immunodeficiency virus type 1 (HIV-1) expression in both CD8-depleted primary leukocytes and chronically infected promonocytic U1 cells stimulated with granulocyte–macrophage colony-stimulating factor (GM-CSF). Activated STAT5Δ can directly bind to two consensus sequences in the HIV-1 long terminal repeat (LTR) promoter; binding impairs recruitment of RNA polymerase II (Crotti, A., Lusic, M., Lupo, R., Lievens, P. M., Liboi, E., Della Chiara, G., et al. (2007). Naturally occurring C-terminally truncated STAT5 is a negative regulator of HIV-1 expression. Blood, 109, 5380–5389). One of the STAT consensus sequences overlaps with one nuclear factor κB (NF-κB) binding site; interestingly, NF-κB1/p50 homodimers, frequently detected in monocytic cells, are negative regulators of HIV transcription. Here, we show that GM-CSF stimulation of U1 cells, while not inducing NF-κB activation, leads to STAT5Δ phosphorylation and binding to the NF-κB/STAT target sequence in the HIV LTR promoter, which already associates with p50 under unstimulated conditions. STAT5Δ was found to associate with p50, but not with RelA/p65, in both U1 cells expressing endogenous proteins and 293T cells overexpressing these factors. Furthermore, GM-CSF stimulation promoted concurrent binding of STAT5Δ and p50 at the HIV LTR promoter in U1 cells. Immunoprecipitation of chromatin from GM-CSF-stimulated U1 cells confirmed in vivo binding of p50 to the viral promoter together with STAT5Δ. Thus, cytokine-activated STAT5Δ/p50 complexes can contribute to the maintenance of HIV-1 latency in monocytic cells.
ISSN:0022-2836
1089-8638
DOI:10.1016/j.jmb.2011.03.044