The Akt1 isoform is required for optimal IFN-β transcription through direct phosphorylation of β-catenin

摘要

Interferon-β (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, of which two are present in macrophages. The specific role for the individual Akt isoforms in pattern recognition and signaling remains unclear. Here we report that the TLR3-mediated expression of IFN-β is blunted in cells lacking 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 Herpes simplex virus-1 (HSV-1) along with reduced IFN-β expression. Our results demonstrate that Akt1 signals through β-catenin by phosphorylation on serine 552, a site that differs from the GSK3-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 serine 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.