B-oligomer of pertussis toxin inhibits HIV-1 LTR-driven transcription through suppression of NF-kappaB p65 subunit activity.
The binding subunit of pertussis toxin (PTX-B) has been shown recently to inhibit the entry and postentry events in HIV-1 replication in primary T lymphocytes and monocyte-derived macrophages. While the effect of PTX-B on HIV-1 entry was shown to involve CCR5 desensitization, the mechanism of postentry inhibition remained unclear. In T lymphocytes, PTX-B affected transcription or stability of Tat-stimulated HIV-1 mRNAs. In this study, we sought to identify the mechanism of postentry inhibition of HIV-1 replication by PTX-B in U-937 promonocytic cells. We demonstrate that in these cells PTX-B inhibits expression of luciferase reporter gene controlled by the HIV-1 LTR promoter. This effect is Tat-independent and is not restricted to the HIV-1 LTR promoter. Instead, PTX-B activity is mediated through suppression of the cellular transcription factor, NF-kappaB. PTX-B inhibits phosphorylation and nuclear translocation of the p65 subunit of NF-kappaB. This effect is independent of the cytoplasmic NF-kappaB inhibitor, IkappaBalpha, as PTX-B stimulates phosphorylation and subsequent degradation of this protein. The suppressive activity of PTX-B on NF-kappaB p65 phosphorylation and nuclear translocation is delayed, suggesting that PTX-B signaling might initiate synthesis and cytoplasmic accumulation of a p65 phosphorylation inhibitor.
Iordanskiy
Sergey
S
The D. I. Ivanovsky Institute of Virology, Russian Academy of Medical Science, Moscow, 123098, Russia.
Iordanskaya
Tatyana
T
Quivy
Vincent
V
Van Lint
Carine
C
Bukrinsky
Michael
M
D001665:Binding Sites; D002467:Cell Nucleus / Q000378:metabolism; D015967:Gene Expression Regulation, Viral / Q000187:drug effects*; D017930:Genes, Reporter; D016325:HIV Long Terminal Repeat / Q000187:drug effects*; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D008156:Luciferases / Q000235:genetics; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D037342:Pertussis Toxin / Q000494:pharmacology*; D010766:Phosphorylation; D051996:Transcription Factor RelA; D014158:Transcription, Genetic / Q000187:drug effects*; D020298:U937 Cells
D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D051996:Transcription Factor RelA; D000072000:NF-KappaB Inhibitor alpha; D008156:Luciferases; D037342:Pertussis Toxin