期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2004
卷号：101
期号：1
页码：233-238
DOI：10.1073/pnas.2237236100
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Virus infection, double-stranded RNA, and lipopolysaccharide each induce the expression of genes encoding IFN- and -{beta} and chemokines, such as RANTES (regulated on activation, normal T cell expressed and secreted) and IP-10 (IFN-{gamma} inducible protein 10). This induction requires the coordinate activation of several transcription factors, including IFN-regulatory factor 3 (IRF3). The signaling pathways leading to IRF3 activation are triggered by the binding of pathogen-specific products to Toll-like receptors and culminate in the phosphorylation of specific serine residues in the C terminus of IRF3. Recent studies of human cell lines in culture have implicated two noncanonical I{kappa}B kinase (IKK)-related kinases, IKK-{varepsilon} and Traf family member-associated NF-{kappa}B activator (TANK)-binding kinase 1 (TBK1), in the phosphorylation of IRF3. Here, we show that purified recombinant IKK-{varepsilon} and TBK1 directly phosphorylate the critical serine residues in IRF3. We have also examined the expression of IRF3-dependent genes in mouse embryonic fibroblasts (MEFs) derived from Tbk1-/- mice, and we show that TBK1 is required for the activation and nuclear translocation of IRF3 in these cells. Moreover, Tbk1-/- MEFs show marked defects in IFN- and -{beta
