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Molecular and Cellular Biology, May 2009, p. 2865-2875, Vol. 29, No. 10
0270-7306/09/$08.00+0     doi:10.1128/MCB.01537-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Interferon-Dependent Engagement of Eukaryotic Initiation Factor 4B via S6 Kinase (S6K)- and Ribosomal Protein S6K-Mediated Signals{triangledown}

Barbara Kroczynska,1 Surinder Kaur,1 Efstratios Katsoulidis,1 Beata Majchrzak-Kita,2 Antonella Sassano,1 Sara C. Kozma,3 Eleanor N. Fish,2 and Leonidas C. Platanias1*

Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Northwestern University Medical School, and Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois 60611,1 Division of Cell and Molecular Biology, Toronto Research Institute, University Health Network and Department of Immunology, University of Toronto, Toronto, Ontario M5G 2M1, Canada,2 Genome Research Institute, University of Cincinnati, Cincinnati, Ohio 452373

Received 2 October 2008/ Returned for modification 21 November 2008/ Accepted 6 March 2009

Although the roles of Jak-Stat pathways in type I and II interferon (IFN)-dependent transcriptional regulation are well established, the precise mechanisms of mRNA translation for IFN-sensitive genes remain to be defined. We examined the effects of IFNs on the phosphorylation/activation of eukaryotic translation initiation factor 4B (eIF4B). Our data show that eIF4B is phosphorylated on Ser422 during treatment of sensitive cells with alpha IFN (IFN-{alpha}) or IFN-{gamma}. Such phosphorylation is regulated, in a cell type-specific manner, by either the p70 S6 kinase (S6K) or the p90 ribosomal protein S6K (RSK) and results in enhanced interaction of the protein with eIF3A (p170/eIF3A) and increased associated ATPase activity. Our data also demonstrate that IFN-inducible eIF4B activity and IFN-stimulated gene 15 protein (ISG15) or IFN-{gamma}-inducible chemokine CXCL-10 protein expression are diminished in S6k1/S6k2 double-knockout mouse embryonic fibroblasts. In addition, IFN-{alpha}-inducible ISG15 protein expression is blocked by eIF4B or eIF3A knockdown, establishing a requirement for these proteins in mRNA translation/protein expression by IFNs. Importantly, the generation of IFN-dependent growth inhibitory effects on primitive leukemic progenitors is dependent on activation of the S6K/eIF4B or RSK/eIF4B pathway. Taken together, our findings establish critical roles for S6K and RSK in the induction of IFN-dependent biological effects and define a key regulatory role for eIF4B as a common mediator and integrator of IFN-generated signals from these kinases.

* Corresponding author. Mailing address: Robert H. Lurie Comprehensive Cancer Center, 303 East Superior Street, Lurie 3-107, Chicago, IL 60611. Phone: (312) 503-4267. Fax: (312) 908-1372. E-mail: l-platanias{at}northwestern.edu

{triangledown} Published ahead of print on 16 March 2009.

Molecular and Cellular Biology, May 2009, p. 2865-2875, Vol. 29, No. 10
0270-7306/09/$08.00+0     doi:10.1128/MCB.01537-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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