Immunology Shifting the Antiviral Response

Nancy R. Gough

Science Signaling, AAAS, Washington, DC 20005, USA

Type I and type II interferons (IFNs) are secreted cytokines that function as a first line of defense against viral infection. IFN-α and IFN-β are type I IFNs and stimulate the formation of a transcriptional regulatory complex called ISGF3 composed of signal transducers and activators of transcription (STAT) proteins STAT1 and STAT2 with IFN regulatory factor 9. IFN- is the type II IFN and stimulates the formation of a STAT1 homodimeric transcription factor complex called GAF. Note that the kinase IKK phosphorylates STAT1 at Ser⁷⁰⁸, and this is important for an effective antiviral response. Ng et al. explored the antiviral response of IKK-deficient mouse embryo fibroblasts (MEFs) and determined that these cells exhibited a reduced IFN type I response and an enhanced IFN type II response compared with wild-type MEFs. Electrophoretic mobility shift assays showed that binding of GAF to cognate DNA sequences was enhanced in IKK-deficient MEFs stimulated with either IFN- or IFN-β; whereas binding of ISGF3 to a subset of its target genes, those known to be IKK-dependent, was reduced. Overexpression of catalytically active, but not inactive, IKK reduced STAT1 homodimerization and stabilized the interaction between STAT1 and STAT2, which would be expected to shift the balance of STAT1 from GAF to ISGF3. Analysis of transcripts from bone marrow–derived macrophages from wild-type and IKK-deficient mice showed that IFN-–regulated genes had increased basal expression, whereas IFN-β–regulated gene expression was lower in cells from the IKK-deficient mice. Chromatin immunoprecipitation experiments confirmed that binding of STAT1 to promoters of genes induced by type I IFNs was reduced, whereas binding of STAT1 to type II IFN-induced genes was unaffected in the absence of IKK. Thus, IKK shifts the antiviral response toward that mediated by type I IFNs by reducing the ability of STAT1 to homodimerize and thus allowing the formation of more ISGF3.

S.-L. Ng, B. A. Friedman, S. Schmid, J. Gertz, R. M. Myers, B. R. tenOever, T. Maniatis, IB kinase (IKK) regulates the balance between type I and type II interferon responses. Proc. Natl. Acad. Sci. U.S.A. 108, 21170–21175 (2011). [Abstract] [Full Text]