The protein kinase Akt1 regulates the interferon response through phosphorylation of the transcriptional repressor EMSY.
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.
Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111, USA.
Scott A
SA
Ezell
Christos
C
Polytarchou
Maria
M
Hatziapostolou
Ailan
A
Guo
Ioannis
I
Sanidas
Teeru
T
Bihani
Michael J
MJ
Comb
George
G
Sourvinos
Philip N
PN
Tsichlis
D016475:3T3 Cells; D000818:Animals; D024682:BRCA2 Protein / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D007372:Interferons / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D044925:Oxidoreductases Acting on CH-CH Group Donors; D011506:Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D014158:Transcription, Genetic; D000090123:Viperin Protein
D024682:BRCA2 Protein; D007372:Interferons; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D044925:Oxidoreductases Acting on CH-CH Group Donors; D011506:Proteins; D051057:Proto-Oncogene Proteins c-akt; D012097:Repressor Proteins; C551750:BRCA2 protein, human; C106711:BRCA2 protein, mouse; C480344:EMSY protein, human; C530774:EMSY protein, mouse; C417529:Rsad2 protein, mouse; D000090123:Viperin Protein; C444427:RSAD2 protein, human