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B Mediate Lipopolysaccharide-Induced HIV-1 Long Terminal Repeat Transcription in Macrophages1
*
Pulmonary Center and Departments of
Pathology and
Microbiology, Boston University School of Medicine, Boston, MA 02118
We recently reported that LPS stimulation of monocytic cells leads
to the activation of PU.1, a member of the Ets family of transcription
factors. Phosphorylation of PU.1 by protein kinase CK2 was found to
up-regulate its trans-activation function, but not its DNA
binding activity. Previous studies suggested that Ets proteins could
bind to NF-
B motifs at the tetrameric core sequence TTCC. In
macrophages, LPS-inducible HIV-1 gene expression is mediated in part by
binding of NF-B to identical tandem binding sites located within the
long terminal repeat (LTR). Thus, we performed additional studies to
determine whether PU.1 also played a role in regulating HIV-1 gene
expression in macrophages. Our functional studies revealed that
activation of the HIV-1 LTR in LPS-stimulated cells requires both
NF-B and PU.1. Extensive mutagenesis of the HIV-1 LTR revealed that
PU.1-dependent activation requires the Ets motif within the upstream
NF-B site, whereas NF-B itself binds to the downstream site. We
also found that insertion of five additional nucleotides between the
NF-B sites abolished LPS inducibility, suggesting a direct
interaction between factors that bind these sites. Lastly, we found
that mutation of PU.1 at serine 148, which prevents its phosphorylation
by CK2, blocked its ability to activate the HIV-1 LTR in response to
LPS. These effects were promoter specific because PU.1 did not affect
LPS-inducible activation of a distinct NF-B-dependent promoter.
While these data do not demonstrate direct binding of PU.1 to the HIV-1
LTR, they illustrate a novel role for PU.1 in activation of the HIV-1
LTR by LPS.
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