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The receptor tyrosine kinase RON represses HIV-1 transcription by targeting RNA polymerase II processivity

Alicia Klatt1, Zhiqiang Zhang, Parisa Kalantari

  • 1Center of Molecular Immunology and Infectious Diseases, Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, PA 16802, USA.

Journal of Immunology (Baltimore, Md. : 1950)
|January 23, 2008
PubMed

Insights

The receptor tyrosine kinase RON inhibits HIV-1 transcription by targeting multiple steps, including initiation and elongation. This cellular signaling pathway represses viral gene expression and may influence proviral latency.

Area of Science:

  • Virology
  • Molecular Biology
  • Cellular Signaling

Background:

  • Efficient HIV-1 transcription needs cellular factors like NF-kappaB and viral Tat to enhance gene expression.
  • The role of cellular signals in repressing HIV-1 transcription and establishing latency is not well understood.
  • The receptor tyrosine kinase RON has been previously shown to inhibit HIV transcription.

Purpose of the Study:

  • To elucidate the biochemical mechanisms by which RON inhibits HIV-1 transcription.
  • To investigate how RON affects transcription factor binding and RNA polymerase II activity at the HIV provirus long terminal repeat.
  • To determine if RON influences chromatin organization and transcription elongation.

Main Methods:

  • Chromatin immunoprecipitation was used to examine transcription factor binding to the HIV provirus long terminal repeat.
  • Analysis of NF-kappaB and RNA polymerase II (Pol II) binding in the presence and absence of RON.
  • Assessment of the impact of RON on transcription elongation factors (NELF, Spt5, Pcf11) and chromatin remodeling.

Main Results:

  • RON expression reduced basal NF-kappaB and Pol II binding to the HIV long terminal repeat.
  • RON did not prevent the induction of these complexes by cytokines but decreased efficient transcription elongation.
  • RON expression correlated with increased binding of negative transcription elongation factors and was sensitive to histone deacetylase inhibitors, indicating effects on chromatin organization.

Conclusions:

  • RON represses HIV-1 transcription at multiple checkpoints: initiation, elongation, and chromatin organization.
  • Cellular signaling pathways, exemplified by RON, can target Pol II pausing to repress gene expression.
  • These findings provide novel insights into the regulation of HIV transcription and potential mechanisms for establishing proviral latency.

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