Candidate tumor suppressor DDX3 RNA helicase specifically represses cap-dependent translation by acting as an eIF4E inhibitory protein.
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.
Shih
J-W
JW
Institute of Biochemistry and Molecular Biology, School of Life Sciences, National Yang-Ming University, Taipei, Taiwan, Republic of China.
Tsai
T-Y
TY
Chao
C-H
CH
Wu Lee
Y-H
YH
D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000502:physiology*; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism*; D016174:Hepacivirus / Q000502:physiology*; D006801:Humans; D017354:Point Mutation; D014176:Protein Biosynthesis; D039381:RNA Cap-Binding Proteins / Q000378:metabolism*; D012270:Ribosomes / Q000502:physiology; D014779:Virus Replication / Q000502:physiology
D039561:Eukaryotic Initiation Factor-4E; D039381:RNA Cap-Binding Proteins; C119332:DDX3X protein, human; D053487:DEAD-box RNA Helicases