Translational control of the innate immune response through IRF-7

Rodney Colina; Mauro Costa-Mattioli; Ryan J.O. Dowling; Maritza Jaramillo; Lee Hwa Tai; Caroline J. Breitbach; Yvan Martineau; Ola Larsson; Liwei Rong; Yuri V. Svitkin; Andrew P. Makrigiannis; John C. Bell; Nahum Sonenberg

doi:10.1038/nature06730

Translational control of the innate immune response through IRF-7

Rodney Colina, Mauro Costa-Mattioli, Ryan J.O. Dowling, Maritza Jaramillo, Lee Hwa Tai, Caroline J. Breitbach, Yvan Martineau, Ola Larsson, Liwei Rong, Yuri V. Svitkin, Andrew P. Makrigiannis, John C. Bell, Nahum Sonenberg

Research output: Contribution to journal › Article › peer-review

270 Citations (Scopus)

Abstract

Transcriptional activation of cytokines, such as type-I interferons (interferon (IFN)-α and IFN-β), 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.

Original language	English
Pages (from-to)	323-328
Number of pages	6
Journal	Nature
Volume	452
Issue number	7185
DOIs	https://doi.org/10.1038/nature06730
Publication status	Published - Mar 20 2008
Externally published	Yes

Bibliographical note

Funding Information:
Acknowledgements We thank M. Karin, M. Gale, R. Lin, W. Sossin, L. W. Ler and A. Rosenfeld for comments on the paper, and N. Taheri, A. Sylvestre and C. Lister for assistance. RIG-I and MDA5 antibodies were provided by H. Kato. This work was supported by a grant from the National Cancer Institute of Canada to N.S. and J.C.B. N.S. is a Howard Hughes Medical Institute (HHMI) International scholar. R.C. is supported by a Cole Foundation post-doctoral fellowship and R.J.O.D. is supported by a Terry Fox Foundation studentship.

ASJC Scopus Subject Areas

General

PubMed: MeSH publication types

Journal Article
Research Support, Non-U.S. Gov't

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@article{989b9733e1f64476b874f21b6d59f886,

title = "Translational control of the innate immune response through IRF-7",

abstract = "Transcriptional activation of cytokines, such as type-I interferons (interferon (IFN)-α and IFN-β), 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.",

author = "Rodney Colina and Mauro Costa-Mattioli and Dowling, {Ryan J.O.} and Maritza Jaramillo and Tai, {Lee Hwa} and Breitbach, {Caroline J.} and Yvan Martineau and Ola Larsson and Liwei Rong and Svitkin, {Yuri V.} and Makrigiannis, {Andrew P.} and Bell, {John C.} and Nahum Sonenberg",

note = "Funding Information: Acknowledgements We thank M. Karin, M. Gale, R. Lin, W. Sossin, L. W. Ler and A. Rosenfeld for comments on the paper, and N. Taheri, A. Sylvestre and C. Lister for assistance. RIG-I and MDA5 antibodies were provided by H. Kato. This work was supported by a grant from the National Cancer Institute of Canada to N.S. and J.C.B. N.S. is a Howard Hughes Medical Institute (HHMI) International scholar. R.C. is supported by a Cole Foundation post-doctoral fellowship and R.J.O.D. is supported by a Terry Fox Foundation studentship.",

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doi = "10.1038/nature06730",

language = "English",

volume = "452",

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T1 - Translational control of the innate immune response through IRF-7

AU - Colina, Rodney

AU - Costa-Mattioli, Mauro

AU - Dowling, Ryan J.O.

AU - Jaramillo, Maritza

AU - Tai, Lee Hwa

AU - Breitbach, Caroline J.

AU - Martineau, Yvan

AU - Larsson, Ola

AU - Rong, Liwei

AU - Svitkin, Yuri V.

AU - Makrigiannis, Andrew P.

AU - Bell, John C.

AU - Sonenberg, Nahum

N1 - Funding Information: Acknowledgements We thank M. Karin, M. Gale, R. Lin, W. Sossin, L. W. Ler and A. Rosenfeld for comments on the paper, and N. Taheri, A. Sylvestre and C. Lister for assistance. RIG-I and MDA5 antibodies were provided by H. Kato. This work was supported by a grant from the National Cancer Institute of Canada to N.S. and J.C.B. N.S. is a Howard Hughes Medical Institute (HHMI) International scholar. R.C. is supported by a Cole Foundation post-doctoral fellowship and R.J.O.D. is supported by a Terry Fox Foundation studentship.

PY - 2008/3/20

Y1 - 2008/3/20

N2 - Transcriptional activation of cytokines, such as type-I interferons (interferon (IFN)-α and IFN-β), 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.

AB - Transcriptional activation of cytokines, such as type-I interferons (interferon (IFN)-α and IFN-β), 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.

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JO - Nature

JF - Nature

IS - 7185

ER -

Translational control of the innate immune response through IRF-7

Abstract

Bibliographical note

ASJC Scopus Subject Areas

PubMed: MeSH publication types

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