Antiviral activity of oligomerization-deficient Stat1.
Interferon stimulation of cells can activate several hundred target genes, many of which are required for antiviral protection. Promoter binding of tyrosine-phosphorylated (activated) Stat1 dimers is essential for gene induction, a process that often entails the oligomerization of Stat1 dimers via interactions of their aminoterminal domains. The mutation of a single residue (F77) in the N-domain of Stat1 was recently demonstrated to preclude both the dephosphorylation and the oligomerization of Stat1 dimers. Here, we investigated the influence of defective oligomerization on a complex phenotype such as the induction of an antiviral state. It was found that the antiviral protection conferred by interferon-a was strongly reduced, whereas the interferon-g response was not measurably affected. These results indicate that Stat1 oligomerization is required for the antiviral activity of interferons. Moreover, the concentration of activated Stat1 in the nucleus may generally play a critical role for interferon-induced target gene activation.
Vinkemeier
Uwe
U
Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Robert-Rössle-Strasse 10, 13125 Berlin, Germany. vinkemeier@fmp-berlin.de
Meyer
Thomas
T
D000998:Antiviral Agents / Q000494:pharmacology; D001665:Binding Sites; D018929:Cell Culture Techniques; D002460:Cell Line; D002461:Cell Line, Transformed; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002472:Cell Transformation, Viral; D003588:Cytopathogenic Effect, Viral / Q000235:genetics*; D019281:Dimerization; D006801:Humans; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit / Q000378:metabolism; D016898:Interferon-alpha / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D010766:Phosphorylation; D017354:Point Mutation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017434:Protein Structure, Tertiary / Q000235:genetics; D050794:STAT1 Transcription Factor / Q000737:chemistry / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D050795:STAT2 Transcription Factor / Q000378:metabolism; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism; D014721:Vesicular stomatitis Indiana virus / Q000187:drug effects; D014779:Virus Replication
D000998:Antiviral Agents; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D016898:Interferon-alpha; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050795:STAT2 Transcription Factor; C494084:STAT2 protein, human; D015534:Trans-Activators; D014443:Tyrosine; D007371:Interferon-gamma