The Akt1 isoform is required for optimal IFN-β transcription through direct phosphorylation of β-catenin.
IFN-β is a critical antiviral cytokine that is capable of modulating the systemic immune response. The transcriptional induction of IFN-β is a highly regulated process, involving the activation of pattern recognition receptors and their downstream signaling pathways. The Akt family of serine/threonine kinases includes three isoforms. The specific role for the individual Akt isoforms in pattern recognition and signaling remains unclear. In this article, we report that the TLR3-mediated expression of IFN-β is blunted in cells that lack Akt1. The expression of IFN-β-inducible genes such as CCL5 and CXCL10 was also reduced in Akt1-deficient cells; the induction of TNF-α and CXCL2, whose expression does not rely on IFN-β, was not reduced in the absence of Akt1. Macrophages from Akt1(-/-) mice displayed deficient clearance of HSV-1 along with reduced IFN-β expression. Our results demonstrate that Akt1 signals through β-catenin by phosphorylation on Ser(552), a site that differs from the glycogen synthase kinase 3 β phosphorylation site. Stimulation of a chemically activated version of Akt1, in the absence of other TLR3-dependent signaling, was sufficient for accumulation and phosphorylation of β-catenin at Ser(552). Taken together, these results demonstrate that the Akt1 isoform is required for β-catenin-mediated promotion of IFN-β transcription downstream of TLR3 activation.
Department of Pharmacology, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA.
Benjamin N
BN
Gantner
Huali
H
Jin
Feng
F
Qian
Nissim
N
Hay
Bin
B
He
Richard D
RD
Ye
D000818:Animals; D006801:Humans; D016899:Interferon-beta / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation / Q000276:immunology; D020033:Protein Isoforms / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D051196:Toll-Like Receptor 3 / Q000378:metabolism; D014158:Transcription, Genetic / Q000276:immunology*; D051176:beta Catenin / Q000378:metabolism* / Q000502:physiology
D020033:Protein Isoforms; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3; D051176:beta Catenin; D016899:Interferon-beta; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt