THE LA ANTIGEN INHIBITS THE ACTIVATION OF THE INTERFERON-INDUCIBLE PROTEIN-KINASE PKR BY SEQUESTERING AND UNWINDING DOUBLE-STRANDED-RNA

The La (SS-B) autoimmune antigen is an RNA-binding protein that is pre sent in both nucleus and cytoplasm of eukaryotic cells. The spectrum o f RNAs that interact with the La antigen includes species which also b ind to the interferon-inducible protein kinase PKR. We have investigat ed whether the La antigen can regulate the activity of PKR and have ob served that both the autophosphorylation of the protein kinase that ac companies its activation by dsRNA and the dsRNA-dependent phosphorylat ion of the alpha subunit of polypeptide chain initiation factor eIF-2 by PKR are inhibited in the presence of recombinant La antigen. This i nhibition is partially relieved at higher concentrations of dsRNA. Onc e activated by dsRNA the protein kinase activity of PKR is insensitive to the La antigen. We have demonstrated by a filter binding assay tha t La is a dsRNA binding protein. Furthermore, when recombinant La is i ncubated with a 900 bp synthetic dsRNA or with naturally occurring reo virus dsRNA it converts these substrates to single-stranded forms. We conclude that the La antigen inhibits the dsRNA-dependent activation o f PKR by binding and unwinding dsRNA and that it may therefore play a role in the regulation of this protein kinase in interferon-treated or virus-infected cells.