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Abstract
The binding of the eukaryotic initiation factor 4E (eIF4E) to the mRNA 5′ cap structure is a rate-limiting step in mRNA translation initiation. eIF4E promotes ribosome recruitment to the mRNA. In Drosophila, the eIF4E homologous protein (d4EHP) forms a complex with binding partners to suppress the translation of distinct mRNAs by competing with eIF4E for binding the 5′ cap structure. This repression mechanism is essential for the asymmetric distribution of proteins and normal embryonic development in Drosophila. In contrast, the physiological role of the mammalian 4EHP (m4EHP) was not known. In this study, we have identified the Grb10-interacting GYF protein 2 (GIGYF2) and the zinc finger protein 598 (ZNF598) as components of the m4EHP complex. GIGYF2 directly interacts with m4EHP, and this interaction is required for stabilization of both proteins. Disruption of the m4EHP-GIGYF2 complex leads to increased translation and perinatal lethality in mice. We propose a model by which the m4EHP-GIGYF2 complex represses translation of a subset of mRNAs during embryonic development, as was previously reported for d4EHP.
SUPPLEMENTAL MATERIAL
Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.00455-12.
ACKNOWLEDGMENTS
We thank D. Labbe, M. Livingstone, and A. Yanagiya for stimulating discussions and C. Lister, I. Harvey, P. Kirk, A. Sylvestre, and S. Perreault for technical assistance.
This work was supported by grants from the Canadian Institute of Health Research (CIHR) and the Canadian Cancer Society (CCS) to N. Sonenberg and from the CIHR (MOP-84314) to A.-C.G., the Uehara Memorial Foundation and the JSPS Excellent Young Researcher Overseas Visit Program to M.M., the CCS to M.F., the Cole Foundation to N. Siddiqui, the Swedish Research Council, the Swedish Cancer Foundation, the Cancer Society in Stockholm, the Jeansson Foundation, and the Åke Wiberg Foundation to O.L., and CIHR and the Terry Fox Research Institute to I.T. A.-C.G. is the Lea Reichmann Chair in Cancer Proteomics and the Canada Research Chair in Functional Proteomics.