A novel 4EHP-GIGYF2 translational repressor complex is essential for mammalian development

Masahiro Morita, Lian Wee Ler, Marc R. Fabian, Nadeem Siddiqui, Michael Mullin, Valerie C. Henderson, Tommy Alain, Bruno D. Fonseca, Galina Karashchuk, Christopher F. Bennett, Tomohiro Kabuta, Shinji Higashi, Ola Larsson, Ivan Topisirovic, Robert J. Smith, Anne Claude Gingras, Nahum Sonenberg

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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.

Original languageEnglish (US)
Pages (from-to)3585-3593
Number of pages9
JournalMolecular and Cellular Biology
Volume32
Issue number17
DOIs
StatePublished - Sep 1 2012

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ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Morita, M., Ler, L. W., Fabian, M. R., Siddiqui, N., Mullin, M., Henderson, V. C., Alain, T., Fonseca, B. D., Karashchuk, G., Bennett, C. F., Kabuta, T., Higashi, S., Larsson, O., Topisirovic, I., Smith, R. J., Gingras, A. C., & Sonenberg, N. (2012). A novel 4EHP-GIGYF2 translational repressor complex is essential for mammalian development. Molecular and Cellular Biology, 32(17), 3585-3593. https://doi.org/10.1128/MCB.00455-12