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Candidate tumor suppressor DDX3 RNA helicase specifically represses cap-dependent translation by acting as an eIF4E inhibitory protein

Oncogene volume 27, pages 700–714 (2008)Cite this article

Abstract

DDX3 is a human RNA helicase with plethoric functions. Our previous studies have indicated that DDX3 is a transcriptional regulator and functions as a tumor suppressor. In this study, we use a bicistronic reporter to demonstrate that DDX3 specifically represses cap-dependent translation but enhances hepatitis C virus internal ribosome entry site-mediated translation in vivo in a helicase activity-independent manner. To elucidate how DDX3 modulates translation, we identified translation initiation factor eukaryotic initiation factor 4E (eIF4E) as a DDX3-binding partner. Interestingly, DDX3 utilizes a consensus eIF4E-binding sequence YIPPHLR to interact with the functionally important dorsal surface of eIF4E in a similar manner to other eIF4E-binding proteins. Furthermore, cap affinity chromatography analysis suggests that DDX3 traps eIF4E in a translationally inactive complex by blocking interaction with eIF4G. Point mutations within the consensus eIF4E-binding motif in DDX3 impair its ability to bind eIF4E and result in a loss of DDX3's regulatory effects on translation. All these features together indicate that DDX3 is a new member of the eIF4E inhibitory proteins involved in translation initiation regulation. Most importantly, this DDX3-mediated translation regulation also confers the tumor suppressor function on DDX3. Altogether, this study demonstrates regulatory roles and action mechanisms for DDX3 in translation, cell growth and likely viral replication.

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Acknowledgements

We are grateful to Dr A Lin and IJ Chen for assistance in polysome profile analysis. We thank Drs MR Chen and LH Hwang for generously providing experimental materials, and Dr R Kirby for critical reading and comments on this paper. This work was supported by the following grants to Dr Y-H Wu Lee: NSC-92-2320-B-010-014, NSC-93-2320-B-010-049, NSC-94-2320-B-010-053 and NSC-95-2320-B-010-012 from the National Science Council as well as NHRI-EX94-9002BL, NHRI-EX95-9501BI and NHRI-EX96-9501BI from the National Health Research Institute and the ‘Aim for the Top University Plan’ grant from the Ministry of Education of the Republic of China.

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  1. Institute of Biochemistry and Molecular Biology, School of Life Sciences, National Yang-Ming University, Taipei, Taiwan, Republic of China

    J-W Shih, T-Y Tsai, C-H Chao & Y-H Wu Lee

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  1. J-W Shih
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Correspondence to Y-H Wu Lee.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Shih, JW., Tsai, TY., Chao, CH. et al. Candidate tumor suppressor DDX3 RNA helicase specifically represses cap-dependent translation by acting as an eIF4E inhibitory protein. Oncogene 27, 700–714 (2008). https://doi.org/10.1038/sj.onc.1210687

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