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The E7 oncoprotein of high-risk human papillomavirus type 16 enters the nucleus via a nonclassical Ran-dependent

Michael Angeline1, Eric Merle, Junona Moroianu

  • 1Biology Department, Boston College, Chestnut Hill, MA 02467, USA.

Virology
|December 17, 2003
PubMed

Insights

The human papillomavirus (HPV) type 16 E7 oncoprotein enters the nucleus through a unique, nonclassical pathway. This import mechanism is Ran-dependent but bypasses conventional import receptors.

Area of Science:

  • Molecular Biology
  • Virology
  • Cell Biology

Background:

  • High-risk human papillomavirus (HPV) oncoproteins, like HPV16 E7, are crucial for viral transformation.
  • HPV16 E7 targets tumor suppressor proteins such as retinoblastoma protein (pRb) and its relatives (p107, p130).
  • HPV16 E7 functions as a nuclear protein but lacks a typical nuclear localization signal, raising questions about its nuclear import mechanism.

Purpose of the Study:

  • To investigate the nuclear import pathway of the HPV16 E7 oncoprotein.
  • To determine if pRb binding is necessary for E7 nuclear import.
  • To characterize the specific import pathway utilized by HPV16 E7.

Main Methods:

  • Utilized digitonin-permeabilized HeLa cells to study nuclear import.
  • Employed a pRb-binding defective E7 variant (E7(DeltaDLYC)) to assess the role of pRb.
  • Investigated the involvement of Ran and classical importin pathways (Kap alpha2beta1, Kap beta1, Kap beta2).
  • Tested the effect of a dominant-negative Ran mutant (RanG19V-GTP) on E7 nuclear import.

Main Results:

  • HPV16 E7 nuclear import occurred independently of its ability to bind pRb.
  • E7 was imported into the nucleus even when pRb binding was abolished.
  • Nuclear import of E7 was found to be Ran-dependent.
  • E7 import was not inhibited by RanG19V-GTP, indicating it does not use the canonical Kap beta-mediated pathways.
  • The data suggest a novel, nonclassical nuclear import pathway for HPV16 E7.

Conclusions:

  • HPV16 E7 utilizes a novel, nonclassical nuclear import pathway.
  • This pathway is distinct from those mediated by major importin-beta family members.
  • The nuclear import of E7 is Ran-dependent but independent of classical importin receptors.

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