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DDX60 selectively reduces translation off viral type II internal ribosome entry sites

Mohammad Sadic1, William M Schneider2, Olga Katsara1

  • 1NYU Grossman School of Medicine, New York, NY, USA.

EMBO Reports
|October 18, 2022
PubMed

Insights

Interferon-stimulated protein DDX60 selectively inhibits viral replication by reducing translation from specific viral RNA structures called type II internal ribosome entry sites (IRESs). This antiviral mechanism targets viral protein synthesis without broadly affecting host cell translation.

Area of Science:

  • Virology
  • Molecular Biology
  • Immunology

Background:

  • Viruses hijack host protein synthesis for replication.
  • Host defense mechanisms often globally inhibit mRNA translation, impacting host cells.
  • Interferon-stimulated genes play a crucial role in antiviral immunity.

Purpose of the Study:

  • To identify and characterize host factors that selectively inhibit viral translation.
  • To investigate the role of the interferon-stimulated helicase DDX60 in antiviral defense.
  • To elucidate the mechanism by which DDX60 restricts viral replication.

Main Methods:

  • Investigated the effect of DDX60 on translation from different types of internal ribosome entry sites (IRESs).
  • Assessed viral replication of encephalomyocarditis virus (EMCV), foot and mouth disease virus (FMDV), poliovirus, and bovine enterovirus 1 (BEV-1) in the presence of DDX60.
  • Analyzed ribosome occupancy on viral IRES and 5' cap-dependent mRNAs.

Main Results:

  • DDX60 selectively inhibits translation from type II IRESs (EMCV, FMDV), but not other IRES types or 5' cap-dependent translation.
  • DDX60 reduces the replication of viruses utilizing type II IRESs (EMCV, FMDV), but not those with type I IRESs (poliovirus, BEV-1).
  • Replacing poliovirus IRES with a type II IRES rendered it sensitive to DDX60 inhibition.
  • DDX60 modulates ribosome loading specifically on type II IRES mRNAs.

Conclusions:

  • DDX60 is an interferon-stimulated gene product that acts as a selective antiviral factor.
  • DDX60 inhibits viral replication by downregulating translation initiated from type II IRES elements.
  • This study reveals a novel mechanism of innate antiviral immunity targeting specific viral RNA structures.
Keywords:
DExDH box helicaseIRESinterferonprotein synthesis

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