Translational control of the innate immune response through IRF-7.
Transcriptional activation of cytokines, such as type-I interferons (interferon (IFN)-alpha and IFN-beta), constitutes the first line of antiviral defence. Here we show that translational control is critical for induction of type-I IFN production. In mouse embryonic fibroblasts lacking the translational repressors 4E-BP1 and 4E-BP2, the threshold for eliciting type-I IFN production is lowered. Consequently, replication of encephalomyocarditis virus, vesicular stomatitis virus, influenza virus and Sindbis virus is markedly suppressed. Furthermore, mice with both 4E- and 4E-BP2 genes (also known as Eif4ebp1 and Eif4ebp2, respectively) knocked out are resistant to vesicular stomatitis virus infection, and this correlates with an enhanced type-I IFN production in plasmacytoid dendritic cells and the expression of IFN-regulated genes in the lungs. The enhanced type-I IFN response in 4E-BP1-/- 4E-BP2-/- double knockout mouse embryonic fibroblasts is caused by upregulation of interferon regulatory factor 7 (Irf7) messenger RNA translation. These findings highlight the role of 4E-BPs as negative regulators of type-I IFN production, via translational repression of Irf7 mRNA.
Colina
Rodney
R
Department of Biochemistry and McGill Cancer Center, McGill University, Montreal, Quebec H3G 1Y6, Canada.
Costa-Mattioli
Mauro
M
Dowling
Ryan J O
RJ
Jaramillo
Maritza
M
Tai
Lee-Hwa
LH
Breitbach
Caroline J
CJ
Martineau
Yvan
Y
Larsson
Ola
O
Rong
Liwei
L
Svitkin
Yuri V
YV
Makrigiannis
Andrew P
AP
Bell
John C
JC
Sonenberg
Nahum
N
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology; D004622:Embryo, Mammalian / Q000166:cytology; D039642:Eukaryotic Initiation Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000821:virology; D017353:Gene Deletion; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology*; D050839:Interferon Regulatory Factor-7 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D007370:Interferon Type I / Q000096:biosynthesis / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014721:Vesicular stomatitis Indiana virus / Q000502:physiology; D018406:Virus Physiological Phenomena; D014779:Virus Replication
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C499527:Eif4ebp1 protein, mouse; C491255:Eif4ebp2 protein, mouse; D039642:Eukaryotic Initiation Factors; D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I; D010750:Phosphoproteins; D012333:RNA, Messenger