Differential regulation of IKK alpha-mediated activation of IRF3/7 by NIK.
Type I interferons (IFNs) are critical mediators of the innate immune system to defend viral infection. Interferon regulatory factor (IRF) 3 and IRF7 are transcription factors that play critical roles in type I IFN production in response to viral infection. It has been shown that the protein kinase I kappaB kinase alpha (IKK alpha) is critically involved in IRF7 activation and IFN-alpha production in Toll-like receptor 7/9 (TLR7/9) signaling cascades. However, overexpression of IKK alpha does not activate the IFN-alpha promoters. Here we show that the protein kinase nuclear factor kappaB-inducing kinase (NIK) confers IKK alpha the ability to activate IRF3/7. Previous studies have shown that NIK phosphorylates IKK alpha at Ser-176 and Ser-180 residues, and mutation of each of the two residues to glutamate, which mimics its phosphorylation, caused constitutive activation of NF-kappaB. However, mutation of the two serine residues has differential effects on IKK alpha-mediated activation of IRF3/7. While IKK alpha(S176E) constitutively activates IRF3/7, IKK alpha(S180E) losses its ability to activate IRF3/7. These findings suggest that IKK alpha-mediated activation of NF-kappaB and IRF3/7 are differentially regulated by NIK, and NIK plays an important role in TLR7/9-mediated IFN-alpha production.
Wang
Rui-Peng
RP
College of Life Sciences, Peking University, Beijing, China.
Zhang
Min
M
Li
Ying
Y
Diao
Fei-Ci
FC
Chen
Danying
D
Zhai
Zhonghe
Z
Shu
Hong-Bing
HB
D000818:Animals; D000998:Antiviral Agents; D002460:Cell Line; D005786:Gene Expression Regulation; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000378:metabolism*; D050839:Interferon Regulatory Factor-7 / Q000235:genetics / Q000378:metabolism*; D007370:Interferon Type I / Q000235:genetics; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D000097782:NF-kappaB-Inducing Kinase
D000998:Antiviral Agents; D051550:I-kappa B Kinase; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I; D053594:Myeloid Differentiation Factor 88; D010768:Phosphoserine; D017346:Protein Serine-Threonine Kinases; D048029:TNF Receptor-Associated Factor 6; D000097782:NF-kappaB-Inducing Kinase