Involvement of the double-stranded-RNA-dependent kinase PKR in interferon expression and interferon-mediated antiviral activity

Proc Natl Acad Sci U S A. 1995 Sep 12;92(19):8841-5. doi: 10.1073/pnas.92.19.8841.

Abstract

The signaling mechanisms responsible for the induced expression of interferon (IFN) genes by viral infection or double-stranded RNA (dsRNA) are not well understood. Here we investigate the role of the interferon-induced dsRNA-dependent protein kinase PKR in the regulation of IFN induction. Biological activities attributed to PKR include regulating protein synthesis, mediating IFN actions, and functioning as a possible tumor suppressor. Since binding of dsRNA is required for its activation, PKR has been considered as a candidate signal transducer for regulating IFN expression. To examine this role of PKR, loss-of-function phenotypes in stable transformants of promonocytic U-937 cells were achieved by two different strategies, overexpression of an antisense PKR transcript or a dominant negative PKR mutant gene. Both types of PKR-deficient cells were more permissive for viral replication than the control U-937 cells. As the result of PKR loss, they also showed impaired induction of IFN-alpha and IFN-beta genes in response to several inducers--specifically, encephalomyocarditis virus, lipopolysaccharide, and phorbol 12-myristate 13-acetate. Interestingly, while IFN-alpha induction by dsRNA was impaired in PKR-deficient cells, IFN-beta induction remained intact. Loss of PKR function also resulted in decreased antiviral activity as elicited by IFN-alpha and, to a greater extent, by IFN-gamma. These results implicate PKR in the regulation of several antiviral activities.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • DNA, Antisense
  • Encephalomyocarditis virus / drug effects
  • Encephalomyocarditis virus / growth & development*
  • Gene Expression Regulation*
  • Humans
  • Interferon-alpha / biosynthesis
  • Interferon-alpha / pharmacology
  • Interferon-beta / biosynthesis
  • Interferon-beta / pharmacology
  • Interferons / biosynthesis*
  • Interferons / pharmacology*
  • Molecular Sequence Data
  • Monocytes / enzymology
  • Monocytes / metabolism
  • Mutation
  • Protein Serine-Threonine Kinases / biosynthesis*
  • Protein Serine-Threonine Kinases / deficiency
  • Protein Serine-Threonine Kinases / genetics
  • Suppression, Genetic
  • Virus Replication / drug effects
  • eIF-2 Kinase

Substances

  • DNA, Antisense
  • Interferon-alpha
  • Interferon-beta
  • Interferons
  • Protein Serine-Threonine Kinases
  • eIF-2 Kinase