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Cellular and Molecular Life Sciences

, Volume 67, Issue 14, pp 2491–2506 | Cite as

Endocytosis of hepatitis C virus non-enveloped capsid-like particles induces MAPK–ERK1/2 signaling events

  • Konstantina Katsarou
  • Alexandros Α. Lavdas
  • Panagiota Tsitoura
  • Elisavet Serti
  • Panagiotis Markoulatos
  • Penelope Mavromara
  • Urania GeorgopoulouEmail author
Research Article

Abstract

Although HCV is an enveloped virus, naked nucleocapsids have been reported in the serum of infected patients. The HCV core particle serves as a protective capsid shell for the viral genome and recombinant in vitro assembled HCV core particles induce strong specific immunity. We investigated the post-binding mechanism of recombinant core particle uptake and its intracellular fate. In hepatic cells, these particles are internalized, most likely in a clathrin-dependent pathway, reaching early to late endosomes and finally lysosomes. The endocytic acidic milieu is implicated in trafficking process. Using specific phosphoantibodies, signaling pathway inhibitors and chemical agents, ERK1/2 was found to be activated in a sustained way after endocytosis, followed by downstream immediate early genes (c-fos and egr-1) modulation. We propose that the intriguing properties of cellular internalization of HCV non-enveloped particles can induce specific ERK1/2–MAPKs events that could be important in HCV life cycle and pathogenesis of HCV infection.

Keywords

Hepatitis C virus Non-enveloped particles Endocytosis ERK1/2 c-fos egr-1 

Notes

Acknowledgments

We thank P. Foka for useful discussions and Dr. D. Blaas for critical reading. We also thank our colleague Dr. K. Lazaridis (Department of Biochemistry, Hellenic Pasteur Institute) for assisting in statistical analysis. This work was supported by PENED 03EΔ297, co-financed by E.U.-European Social Fund (75%) and the Greek Ministry of Development-GSRT (25%).

Supplementary material

HCVne particles in HepG2 cells follow an indentical progression from early to late endosomes and lysosomes. Cells were incubated with HCVne particles for 15 minutes or 4 hours and immunostained with anti-core (green) and anti-EEA1/anti-Lamp2 (red). Cells were also transfected with mRFP-Rab7 (red). 24 hours post-transfection HCVne particles were added for 1 hour, and cells were fixed and immunostained for anti-core (green). Colocalization is observed in yellow. Bars:8μm (MPG 3701 kb)

18_2010_351_MOESM2_ESM.mpg (908 kb)
HCVne particles in endosomes use actin filaments and microtubules for their traffic. A) HCVne particles were added for 15 minutes in Huh7 cells which were fixed and immunolabeled with anti-core (green) / anti-EEA1 (blue) antibodies and counterstained with Alexa 546-phalloidin. B) Huh7 cells where transfected with mRFP-Rab5. 24 hours post-transfection, cells were incubated with HCVne for 15 minutes, immunostained with anti-core (green) and anti-α tubulin (blue). Parts of cells are presented and a triple colocalization (white spot) is observed (MPG 908 kb)
18_2010_351_MOESM3_ESM.tif (460 kb)
HCVne particles colocalize with early endosomes. Dual-color live fluorescence microscopy experiment recorded in Huh7 cells transfected with mRFP-Rab5 (red) in the presence of green fluorescent GFP-HCVne particles described in (14). One picture every 10 second was recorded with a 100x objective at 37oC for 20 minutes after recombinant HCVne binding (TIFF 459 kb)
18_2010_351_MOESM4_ESM.tif (1.5 mb)
HCVne particles colocalize with late endosomes. Live Huh7 cells transfected with mRFP-Rab7 (red) and challenged with green fluorescent GFP-HCVne particles (14). Video was recorded 30 minutes after particles were added with 60x objective at 37oC for 30 minutes (one picture every 30 seconds). Time elapsed from the beginning of recording is noted in each frame of figure 2C (TIFF 1582 kb)

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Copyright information

© Springer Basel AG 2010

Authors and Affiliations

  • Konstantina Katsarou
    • 1
  • Alexandros Α. Lavdas
    • 2
  • Panagiota Tsitoura
    • 3
  • Elisavet Serti
    • 1
  • Panagiotis Markoulatos
    • 4
  • Penelope Mavromara
    • 1
  • Urania Georgopoulou
    • 1
    Email author
  1. 1.Molecular Virology LaboratoryHellenic Pasteur InstituteAthensGreece
  2. 2.Laboratory of Cellular and Molecular NeurobiologyHellenic Pasteur InstituteAthensGreece
  3. 3.Insect Molecular Genetics and Biotechnology, Institute of BiologyNCSR DemokritosAthensGreece
  4. 4.Department of Biochemistry and BiotechnologyUniversity of ThessalyThessalyGreece

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