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PNAS 109 (10): 613-621

Copyright © 2012 by the National Academy of Sciences.

PNAS Plus


PNAS PLUS / BIOLOGICAL SCIENCES / IMMUNOLOGY

The protein kinase Akt1 regulates the interferon response through phosphorylation of the transcriptional repressor EMSY

Scott A. Ezella,b, Christos Polytarchoua,1, Maria Hatziapostoloua,1, Ailan Guoc, Ioannis Sanidasa, Teeru Bihania, Michael J. Combc, George Sourvinosa,d, and Philip N. Tsichlisa,b,2

aMolecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111; bSackler School of Graduate Biomedical Studies, Tufts University, Boston, MA 02111; c Cell Signaling Technology, Danvers, MA 01923; and d Laboratory of Virology, University of Crete Medical School, Heraklion 71003, Crete, Greece

2To whom correspondence should be addressed. E-mail: ptsichlis{at}tuftsmedicalcenter.org.

Abstract: The protein kinases Akt1, Akt2, and Akt3 possess nonredundant signaling properties, few of which have been investigated. Here, we present evidence for an Akt1-dependent pathway that controls interferon (IFN)-regulated gene expression and antiviral immunity. The target of this pathway is EMSY, an oncogenic interacting partner of BRCA2 that functions as a transcriptional repressor. Overexpression of EMSY in hTERT-immortalized mammary epithelial cells, and in breast and ovarian carcinoma cell lines, represses IFN-stimulated genes (ISGs) in a BRCA2-dependent manner, whereas its knockdown has the opposite effect. EMSY binds to the promoters of ISGs, suggesting that EMSY functions as a direct transcriptional repressor. Akt1, but not Akt2, phosphorylates EMSY at Ser209, relieving EMSY-mediated ISG repression. The Akt1/EMSY/ISG pathway is activated by both viral infection and IFN, and it inhibits the replication of HSV-1 and vesicular stomatitis virus (VSV). Collectively, these data define an Akt1-dependent pathway that contributes to the full activation of ISGs by relieving their repression by EMSY and BRCA2.

Key Words: ISG15 • IFITM1 • RSAD2 • Viperin • viral replication


 

Conflict of interest statement: A.G. and M.J.C. are employees of Cell Signaling Technology.

This article is a PNAS Direct Submission.

See full research article on page E613 of www.pnas.org.

Cite this Author Summary as: PNAS 10.1073/pnas.1115029109.


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