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J. Biol. Chem., Vol. 282, Issue 3, 1757-1768, January 19, 2007

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Regulatory Effects of Mammalian Target of Rapamycin-activated Pathways in Type I and II Interferon Signaling^*

Surinder Kaur, Lakhvir Lal, Antonella Sassano, Beata Majchrzak-Kita, Maya Srikanth, Darren P. Baker^¶, Emmanuel Petroulakis^||, Nissim Hay^**, Nahum Sonenberg^||, Eleanor N. Fish, and Leonidas C. Platanias¹

From the Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Northwestern University Medical School and Lakeside Veterans Affairs Medical Center, Chicago, Illinois 60611, the Division of Cell and Molecular Biology, Toronto Research Institute, University Health Network and Department of Immunology, University of Toronto, Toronto, Ontario M5G2M1, Canada, ^¶Biogen Idec Inc., Cambridge, Massachusetts 02142, the ^||Department of Biochemistry, McGill University, Montreal, Quebec H3G1Y6, Canada, and the ^**Department of Molecular Genetics, University of Illinois, Chicago, Illinois 60607

The mechanisms regulating initiation of mRNA translation for the generation of protein products that mediate interferon (IFN) responses are largely unknown. We have previously shown that both Type I and II IFNs engage the mammalian target of rapamycin (mTOR), resulting in downstream phosphorylation and deactivation of the translational repressor 4E-BP1 (eIF4E-binding protein 1). In the current study, we provide direct evidence that such regulation of 4E-BP1 by IFN or IFN results in sequential dissociation of 4E-BP1 from eukaryotic initiation factor-4E and subsequent formation of a functional complex between eukaryotic initiation factor-4E and eukaryotic initiation factor-4G, to allow initiation of mRNA translation. We also demonstrate that the induction of key IFN- or IFN-inducible proteins (ISG15 (interferon-stimulated gene 15) and CXCL10) that mediate IFN responses are enhanced in 4E-BP1 (4E-BP1^-/-) knockout MEFs, as compared with wild-type 4E-BP1^+/+ MEFs. On the other hand, IFN-dependent transcriptional regulation of the Isg15 and Cxcl10 genes is intact in the absence of 4E-BP1, as determined by real time reverse transcriptase-PCR assays and promoter assays for ISRE and GAS, establishing that 4E-BP1 plays a selective negative regulatory role in IFN-induced mRNA translation. Interestingly, the induction of expression of ISG15 and CXCL10 proteins by IFNs was also strongly enhanced in cells lacking expression of the tuberin (TSC2^-/-) or hamartin (TSC1^-/-) genes, consistent with the known negative regulatory effect of the TSC1-TSC2 complex on mTOR activation. In other work, we demonstrate that the induction of an IFN-dependent antiviral response is strongly enhanced in cells lacking expression of 4E-BP1 and TSC2, demonstrating that these elements of the IFN-activated mTOR pathway exhibit important regulatory effects in the generation of IFN responses. Taken altogether, our data suggest an important role for mTOR-dependent pathways in IFN signaling and identify 4E-BP1 and TSC1-TSC2 as key components in the generation of IFN-dependent biological responses.

Received for publication, August 3, 2006 , and in revised form, November 17, 2006.

^* This work was supported by National Institutes of Health Grants CA77816, CA100579, and CA94079 (to L. C. P.), by a grant from the Department of Veterans Affairs (to L. C. P.), and Canadian Institutes of Health Research Grant MOP15094 (to E. N. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Robert H. Lurie Comprehensive Cancer Center, 303 E. Superior St., Lurie 3-107, Chicago, IL 60611. Tel.: 312-503-4267; Fax: 312-908-1372; E-mail: l-platanias{at}northwestern.edu.

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