Triggering the Interferon Antiviral Response Through an IKK-Related Pathway

Lady Davis Institute for Medical Research-Jewish General Hospital, Departments of Microbiology and Immunology and Medicine, McGill University, Montreal, Quebec H3T 1E2, Canada.
Science (Impact Factor: 33.61). 06/2003; 300(5622):1148-51. DOI: 10.1126/science.1081315
Source: PubMed


Rapid induction of type I interferon expression, a central event in establishing the innate antiviral response, requires cooperative
activation of numerous transcription factors. Although signaling pathways that activate the transcription factors nuclear
factor κB and ATF-2/c-Jun have been well characterized, activation of the interferon regulatory factors IRF-3 and IRF-7 has
remained a critical missing link in understanding interferon signaling. We report here that the IκB kinase (IKK)–related kinases
IKKϵ and TANK-binding kinase 1 are components of the virus-activated kinase that phosphorylate IRF-3 and IRF-7. These studies
illustrate an essential role for an IKK-related kinase pathway in triggering the host antiviral response to viral infection.

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    • "This observation is consistent with a previous report that 17β-estradiol can enhance the ability of STAT1 to bind to ISRE [66]. Multiple studies have reported that IKKε phosphorylates specific serine residues in the transcription factors IRF3 and IRF7 in response to virus infection [67] [68] and promotes formation of the IFN-β enhanceosome [69]. Interestingly, the severity and incidence of innate immune conditions, such as sepsis and post-surgery infections, are profoundly less in women compared with age-matched men [70] [71]. "
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    • "Among the genes whose expression was found defective in the absence of Ulk1/2 were Cxcl10 (Zhang et al., 2005) and Eif2ak2 (García et al., 2006; McAllister and Samuel, 2009), both of which are involved in the induction of antiviral effects and control of apoptosis. The induction of several other genes whose function was necessary for generation for IFN biological responses was also defective in Ulk1/2 À/À cells, including Irgm2 (Hunn et al., 2008), Gch1 (Rani et al., 2007; Alp and Channon , 2004), Ifit3 (Schmeisser et al., 2010; Liu et al., 2011); Oasl2 (Zhu et al., 2014), Irf7 (Sharma et al., 2003; Honda et al., 2005; Colina et al., 2008), Irf9 (Darnell et al., 1994; van Boxel-Dezaire et al., 2006), and Isg54/Ifit2 (Yang et al., 2012) (Figures 3A–3I). "
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    • "Represses TGF-b-Induced Transcription RLR-induced IRF3 activation results from the activities of TBK1 or IKKε that phosphorylate and thus activate IRF3 (Fitzgerald et al., 2003; Sharma et al., 2003). BX795, an inhibitor of TBK1 and IKKε (Clark et al., 2009), inhibited the activation of IRF3 (Figure 2A, 4 th lane), and restored the inhibition of TGF-b-induced transcription by TpIC (Figure 2B, lanes 3, 4). "
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