The receptor tyrosine kinase RON represses HIV-1 transcription by targeting RNA polymerase II processivity.
Efficient HIV-1 transcription requires the induction of cellular transcription factors, such as NF-kappaB, and the viral factor Tat, which through the recruitment of P-TEFb enhances processive transcription. However, whether cellular signals repress HIV-1 transcription to establish proviral latency has not been well studied. Previously, it has been shown that the receptor tyrosine kinase RON inhibits HIV transcription. To gain insights into the biochemical mechanisms by which RON inhibits transcription we examined the binding of transcription factors to the HIV provirus long terminal repeat using chromatin immunoprecipitation. RON expression decreased basal levels of NF-kappaB and RNA polymerase II (Pol II) binding to the HIV provirus long terminal repeat but did not prevent the induction of these complexes following treatment with cytokines. However, RON did decrease efficient transcription elongation because reduced RNA Pol II was associated with HIV-1 genomic sequences downstream of the transcriptional start site. There was a correlation between RON expression and increased binding of factors that negatively regulate transcription elongation, NELF, Spt5, and Pcf11. Furthermore, the ability of RON to inhibit HIV-1 transcription was sensitive to a histone deacetylase inhibitor and was associated with nucleosome remodeling. These results indicate that RON represses HIV transcription at multiple transcriptional check points including initiation, elongation and chromatin organization and are the first studies to show that cellular signaling pathways target Pol II pausing to repress gene expression.
Klatt
Alicia
A
Center of Molecular Immunology and Infectious Diseases, Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, PA 16802, USA.
Zhang
Zhiqiang
Z
Kalantari
Parisa
P
Hankey
Pamela A
PA
Gilmour
David S
DS
Henderson
Andrew J
AJ
D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D015967:Gene Expression Regulation, Viral; D016325:HIV Long Terminal Repeat; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009707:Nucleosomes / Q000378:metabolism; D012319:RNA Polymerase II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D014158:Transcription, Genetic
D016328:NF-kappa B; D009707:Nucleosomes; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases; D012319:RNA Polymerase II