TY - JOUR
T1 - Importin 8 mediates m7G cap-sensitive nuclear import of the eukaryotic translation initiation factor eIF4E
AU - Volpon, Laurent
AU - Culjkovic-Kraljacic, Biljana
AU - Osborne, Michael J.
AU - Ramteke, Anup
AU - Sun, Qingxiang
AU - Niesman, Ashley
AU - Chook, Yuh Min
AU - Borden, Katherine L B
N1 - Funding Information:
This research was supported by NIH Grants R01 98571 and R01 80728; Translational Research Program grants from the Leukemia and Lymphoma Society (to K.L.B.B.); NIH Grants R01 GM069909 (to Y.M.C.) and U01 GM98526 (to Y.M.C.); the University of Texas Southwestern Endowed Scholars Program (Y.M.C.); Welch Foundation Grant I-1532 (to Y.M.C.); and a Leukemia and Lymphoma Society Scholar Award (to Y.M.C.). K.L.B.B. holds a Canada Research Chair.
PY - 2016/5/10
Y1 - 2016/5/10
N2 - 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 (m7G)-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 m7G-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 capfree eIF4E. Cap-dependent changes to the structure of eIF4E underpin this selectivity. Indeed, m7G 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.
AB - 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 (m7G)-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 m7G-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 capfree eIF4E. Cap-dependent changes to the structure of eIF4E underpin this selectivity. Indeed, m7G 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.
KW - EIF4E
KW - Importin 8
KW - MG cap
KW - Nuclear import
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U2 - 10.1073/pnas.1524291113
DO - 10.1073/pnas.1524291113
M3 - Article
C2 - 27114554
AN - SCOPUS:84966430628
SN - 0027-8424
VL - 113
SP - 5263
EP - 5268
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 19
ER -