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Polysome Fractionation and Analysis of Mammalian Translatomes on a Genome-wide Scale
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Assessment of mTOR-Dependent Translational Regulation of Interferon Stimulated Genes

Mark Livingstone1, Kristina Sikström2, Philippe A Robert1

  • 1Cytokine Signaling Unit, Institut Pasteur, CNRS URA1961, Paris, France.

Plos One
|July 25, 2015
PubMed

Insights

Type-I interferon (IFN) does not selectively control most interferon-stimulated gene (ISG) mRNA translation via the mTOR pathway. However, one ISG mRNA shifts to mTOR-sensitive translation by altering its 5' untranslated region.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Biology

Background:

  • Type-I interferon (IFN) signaling activates the mammalian target of rapamycin (mTOR) pathway, impacting protein synthesis.
  • mTOR-sensitive translatomes typically contain 5' terminal oligopyrimidine tract (TOP) mRNAs, like those for ribosomal proteins, but not interferon-stimulated genes (ISGs).

Purpose of the Study:

  • To investigate the mTOR-sensitive translatome of ISG mRNAs under IFN-β stimulation.
  • To elucidate the translational control mechanisms of ISG mRNAs in response to Type-I IFN.

Main Methods:

  • Human WISH cells were stimulated with IFN-β.
  • The mTOR inhibitor Torin1 was used to assess global protein synthesis and specific ISG mRNA translation.
  • Detailed analysis of NT5C3A mRNA identified changes in its 5' untranslated region (5'-UTR).

Main Results:

  • IFN-β stimulation did not result in selective mTOR-sensitive translation for most ISG mRNAs.
  • Torin1 treatment repressed global protein synthesis, including ISG products.
  • NT5C3A mRNA exhibited an IFN-induced shift from a non-TOP to a TOP-like variant, rendering its translation mTOR-sensitive.

Conclusions:

  • The translation of most ISG mRNAs is not selectively sensitive to mTOR activity during Type-I IFN response.
  • An uncharacterized mechanism involves cytokine-induced alteration of an mRNA's 5'-UTR, switching its translation from mTOR-insensitive to mTOR-sensitive.

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