Robust expression of vault RNAs induced by influenza A virus plays a critical role in suppression of PKR-mediated innate immunity

Nucleic Acids Res. 2015 Dec 2;43(21):10321-37. doi: 10.1093/nar/gkv1078. Epub 2015 Oct 20.


Protein kinase R (PKR) is a vital component of host innate immunity against viral infection. However, the mechanism underlying inactivation of PKR by influenza A virus (IAV) remains elusive. Here, we found that vault RNAs (vtRNAs) were greatly induced in A549 cells and mouse lungs after infection with IAV. The viral NS1 protein was shown to be the inducer triggering the upregulation of vtRNAs. Importantly, silencing vtRNA in A549 cells significantly inhibited IAV replication, whereas overexpression of vtRNAs markedly promoted the viral replication. Furthermore, in vivo studies showed that disrupting vtRNA expression in mice significantly decreased IAV replication in infected lungs. The vtRNA knockdown animals exhibited significantly enhanced resistance to IAV infection, as evidenced by attenuated acute lung injury and spleen atrophy and consequently increased survival rates. Interestingly, vtRNAs promoted viral replication through repressing the activation of PKR and the subsequent antiviral interferon response. In addition, increased expression of vtRNAs was required for efficient suppression of PKR by NS1 during IAV infection. Moreover, vtRNAs were also significantly upregulated by infections of several other viruses and involved in the inactivation of PKR signaling by these viruses. These results reveal a novel mechanism by which some viruses circumvent PKR-mediated innate immunity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Disease Resistance
  • Female
  • Humans
  • Immunity, Innate*
  • Influenza A virus / physiology*
  • Interferons / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Orthomyxoviridae Infections / genetics*
  • Orthomyxoviridae Infections / immunology
  • Orthomyxoviridae Infections / metabolism
  • RNA, Untranslated / metabolism*
  • Viral Nonstructural Proteins / metabolism
  • Virus Replication
  • eIF-2 Kinase / metabolism*


  • INS1 protein, influenza virus
  • RNA, Untranslated
  • Viral Nonstructural Proteins
  • Interferons
  • eIF-2 Kinase