Importin 8 mediates m7G cap-sensitive nuclear import of the eukaryotic translation initiation factor eIF4E.
Regulation of nuclear-cytoplasmic trafficking of oncoproteins is critical for growth homeostasis. Dysregulated trafficking contributes to malignancy, whereas understanding the process can reveal unique therapeutic opportunities. Here, we focus on eukaryotic translation initiation factor 4E (eIF4E), a prooncogenic protein highly elevated in many cancers, including acute myeloid leukemia (AML). Typically, eIF4E is localized to both the nucleus and cytoplasm, where it acts in export and translation of specific methyl 7-guanosine (m(7)G)-capped mRNAs, respectively. Nuclear accumulation of eIF4E in patients who have AML is correlated with increased eIF4E-dependent export of transcripts encoding oncoproteins. The subcellular localization of eIF4E closely correlates with patients' responses. During clinical responses to the m(7)G-cap competitor ribavirin, eIF4E is mainly cytoplasmic. At relapse, eIF4E reaccumulates in the nucleus, leading to elevated eIF4E-dependent mRNA export. We have identified importin 8 as a factor that directly imports eIF4E into the nucleus. We found that importin 8 is highly elevated in untreated patients with AML, leading to eIF4E nuclear accumulation. Importin 8 only imports cap-free eIF4E. Cap-dependent changes to the structure of eIF4E underpin this selectivity. Indeed, m(7)G cap analogs or ribavirin prevents nuclear entry of eIF4E, which mirrors the trafficking phenotypes observed in patients with AML. Our studies also suggest that nuclear entry is important for the prooncogenic activity of eIF4E, at least in this context. These findings position nuclear trafficking of eIF4E as a critical step in its regulation and position the importin 8-eIF4E complex as a novel therapeutic target.
Institute of Research in Immunology and Cancer, Department of Pathology and Cell Biology, Université de Montréal, Montreal, QC, H3T 1J4, Canada;
Laurent
L
Volpon
Institute of Research in Immunology and Cancer, Department of Pathology and Cell Biology, Université de Montréal, Montreal, QC, H3T 1J4, Canada;
Biljana
B
Culjkovic-Kraljacic
Institute of Research in Immunology and Cancer, Department of Pathology and Cell Biology, Université de Montréal, Montreal, QC, H3T 1J4, Canada;
Michael J
MJ
Osborne
Institute of Research in Immunology and Cancer, Department of Pathology and Cell Biology, Université de Montréal, Montreal, QC, H3T 1J4, Canada;
Anup
A
Ramteke
Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-9041.
Qingxiang
Q
Sun
Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-9041.
Ashley
A
Niesman
Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-9041.
Yuh Min
YM
Chook
Institute of Research in Immunology and Cancer, Department of Pathology and Cell Biology, Université de Montréal, Montreal, QC, H3T 1J4, Canada; katherine.borden@umontreal.ca.
Katherine L B
KL
Borden
D021581:Active Transport, Cell Nucleus / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism*; D006151:Guanosine / Q000031:analogs & derivatives* / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism*; D029543:Nucleocytoplasmic Transport Proteins / Q000378:metabolism*; D021381:Protein Transport; D014407:Tumor Cells, Cultured; D028961:beta Karyopherins / Q000378:metabolism*
C116616:8-methylguanosine; C411571:EIF4ENIF1 protein, human; C107282:IPO8 protein, human; D029543:Nucleocytoplasmic Transport Proteins; D028961:beta Karyopherins; D006151:Guanosine
eIF4E; importin 8; m7G cap; nuclear import