Importin 8 mediates m7G cap-sensitive nuclear import of the eukaryotic translation initiation factor eIF4E

Laurent Volpon, Biljana Culjkovic-Kraljacic, Michael J. Osborne, Anup Ramteke, Qingxiang Sun, Ashley Niesman, Yuh Min Chook, Katherine L B Borden

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)5263-5268
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number19
DOIs
StatePublished - May 10 2016

Fingerprint

Eukaryotic Initiation Factor-4E
Karyopherins
Eukaryotic Initiation Factors
Cell Nucleus Active Transport
Guanosine
Acute Myeloid Leukemia
Ribavirin
Oncogene Proteins
Messenger RNA

Keywords

  • EIF4E
  • Importin 8
  • MG cap
  • Nuclear import

ASJC Scopus subject areas

  • General

Cite this

Importin 8 mediates m7G cap-sensitive nuclear import of the eukaryotic translation initiation factor eIF4E. / Volpon, Laurent; Culjkovic-Kraljacic, Biljana; Osborne, Michael J.; Ramteke, Anup; Sun, Qingxiang; Niesman, Ashley; Chook, Yuh Min; Borden, Katherine L B.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 113, No. 19, 10.05.2016, p. 5263-5268.

Research output: Contribution to journalArticle

Volpon, Laurent ; Culjkovic-Kraljacic, Biljana ; Osborne, Michael J. ; Ramteke, Anup ; Sun, Qingxiang ; Niesman, Ashley ; Chook, Yuh Min ; Borden, Katherine L B. / Importin 8 mediates m7G cap-sensitive nuclear import of the eukaryotic translation initiation factor eIF4E. In: Proceedings of the National Academy of Sciences of the United States of America. 2016 ; Vol. 113, No. 19. pp. 5263-5268.
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AU - Volpon, Laurent

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AU - Ramteke, Anup

AU - Sun, Qingxiang

AU - Niesman, Ashley

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AU - Borden, Katherine L B

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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.

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