Interferon Signaling

Akting to Derepress Interferon Responses

Science Signaling  13 Mar 2012:
Vol. 5, Issue 215, pp. ec77
DOI: 10.1126/scisignal.2003034

Viral infection induces type I interferons (IFNs), which inhibit viral replication through the expression of IFN-stimulated genes (ISGs). The serine and threonine kinase Akt is activated in response to type I IFNs, and disruption of Akt signaling results in defective ISG expression. Noting that the individual contributions of each of the three isoforms of Akt to the IFN response are poorly understood, Ezell et al. performed a phosphoproteomic screen of proteins in murine lung fibroblasts engineered to express only a single Akt isoform and identified the BRCA2-interacting protein EMSY (a repressor of BRCA2-dependent transcription), which was phosphorylated at Ser209 (S209). Expression of EMSY in transfected human mammary epithelial cells reduced the expression of ISGs; however, expression of EMSY S209A, a mutant that cannot be phosphorylated by Akt, resulted in almost complete suppression of ISG expression. In vitro experiments showed that Akt1, but not Akt2, phosphorylated EMSY at Ser209, inhibiting its physical interaction with BRCA2 and relieving the repression of ISG expression by EMSY. Expression of EMSY reduced the expression of ISGs in cells infected with herpes simplex virus 1 (HSV-1) and promoted viral replication, whereas expression of Akt1 reversed these effects. EMSY is highly abundant in human breast and ovarian cancers, and expression of Akt1 in human breast and ovarian cancer cell lines increased phosphorylation of EMSY at Ser209 and derepressed the expression of ISGs. Together, these data suggest that Ak1 specifically enhances the type I IFN response by targeting EMSY and relieving repression of the expression of BRCA2-dependent ISGs.

S. A. Ezell, C. Polytarchou, M. Hatziapostolou, A. Guo, I. Sanidas, T. Bihani, M. J. Comb, G. Sourvinos, P. N. Tsichlis, The protein kinase Akt1 regulates the interferon response through phosphorylation of the transcriptional repressor EMSY. Proc. Natl. Acad. Sci. U.S.A. 109, E613–E621 (2012). [Abstract] [Full Text]