The hepatitis C virus non-structural protein NS5A alters the trafficking profile of the epidermal growth factor receptor

Traffic. 2008 Sep;9(9):1497-509. doi: 10.1111/j.1600-0854.2008.00779.x. Epub 2008 Jun 9.

Abstract

Hepatitis C virus (HCV) frequently establishes a persistent infection, leading to chronic liver disease. The NS5A protein has been implicated in this process as it modulates a variety of intracellular signalling pathways that control cell survival and proliferation. In particular, NS5A associates with several proteins involved in the endocytosis of the epidermal growth factor receptor (EGFR) and has been previously shown to inhibit epidermal growth factor (EGF)-stimulated activation of the Ras-Erk pathway by a mechanism that remains unclear. As EGFR signalling involves trafficking to late endosomes, we investigated whether NS5A perturbs EGFR signalling by altering receptor endocytosis. We demonstrate that NS5A partially localizes to early endosomes and, although it has no effect on EGF internalization, it colocalizes with the EGFR and alters its distribution. This redistribution correlates with a decrease in the amount of active EGF-EGFR ligand-receptor complexes present in the late endosomal signalling compartment and also results in a concomitant increase in the total levels of EGFR. These observations suggest that NS5A controls EGFR signalling by diverting the receptor away from late endosomes. This represents a novel mechanism by which a viral protein attenuates cell signalling and suggests that NS5A may perturb trafficking pathways to maintain an optimal environment for HCV persistence.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Western
  • Cell Culture Techniques
  • Cell Line, Tumor
  • Cell Membrane / metabolism
  • Cell Membrane / virology
  • Culture Media, Serum-Free
  • Endocytosis / physiology
  • Endosomes / metabolism
  • Endosomes / virology
  • ErbB Receptors / metabolism*
  • Hepacivirus / metabolism*
  • Hepacivirus / pathogenicity
  • Humans
  • Ligands
  • Luciferases / genetics
  • Microscopy, Confocal
  • Protein Transport
  • Signal Transduction
  • Transfection
  • Viral Nonstructural Proteins / genetics
  • Viral Nonstructural Proteins / metabolism
  • Viral Nonstructural Proteins / physiology*

Substances

  • Culture Media, Serum-Free
  • Ligands
  • NS-5 protein, hepatitis C virus
  • Viral Nonstructural Proteins
  • Luciferases
  • ErbB Receptors