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A High Resolution Method to Monitor Phosphorylation-dependent Activation of IRF3
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Tristetraprolin mediates interferon-gamma mRNA decay.

Rachel L Ogilvie1, Julius R Sternjohn, Bernd Rattenbacher

  • 1Centers for Infectious Diseases and Microbiology Translational Research and Immunology, University of Minnesota, Minneapolis, Minnesota 55455, USA.

The Journal of Biological Chemistry
|March 5, 2009
PubMed
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Tristetraprolin (TTP) controls the decay of messenger RNA (mRNA) for cytokines. This study shows TTP binds to interferon-gamma (IFN-gamma) mRNA, promoting its degradation and regulating immune responses.

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Area of Science:

  • Immunology
  • Molecular Biology
  • Gene Regulation

Background:

  • Tristetraprolin (TTP) is known to regulate mRNA decay for certain cytokines, including interleukin-2.
  • The role of TTP in regulating other T cell-specific cytokines, such as interferon-gamma (IFN-gamma), requires further investigation.

Purpose of the Study:

  • To determine if TTP regulates the expression of interferon-gamma (IFN-gamma).
  • To elucidate the mechanism by which TTP influences IFN-gamma mRNA stability and expression.

Main Methods:

  • Comparison of IFN-gamma mRNA and protein levels in TTP knock-out versus wild-type mice following T cell receptor activation.
  • Measurement of IFN-gamma mRNA half-life in activated T cells from both mouse models.
  • Reporter assays using a beta-globin transcript containing the IFN-gamma 3'-untranslated region AU-rich element.

Main Results:

  • TTP knock-out T cells exhibited significantly higher levels of IFN-gamma mRNA and protein upon activation compared to wild-type cells.
  • IFN-gamma mRNA demonstrated increased stability (longer half-life) in TTP knock-out T cells.
  • An AU-rich element from the IFN-gamma 3'-untranslated region conferred TTP-dependent mRNA destabilization on a reporter transcript.

Conclusions:

  • TTP binds to a functional AU-rich element within the 3'-untranslated region of IFN-gamma mRNA.
  • TTP actively promotes the rapid degradation of IFN-gamma mRNA.
  • TTP plays a critical role in the timely termination of IFN-gamma expression during immune responses.