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Journal of Virology, August 2004, p. 7958-7968, Vol. 78, No. 15
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.15.7958-7968.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Targeting of Hepatitis C Virus Core Protein to Mitochondria through a Novel C-Terminal Localization Motif{ddagger}

Björn Schwer,1 Shaotang Ren,2 Thomas Pietschmann,3,{dagger} Jürgen Kartenbeck,1,{dagger} Katrin Kaehlcke,1,4 Ralf Bartenschlager,3 T. S. Benedict Yen,2,5,6 and Melanie Ott1,4,6*

Deutsches Krebsforschungszentrum (DKFZ),1 Department of Molecular Virology, University of Heidelberg, Heidelberg, Germany,3 Pathology Service, Veterans Affairs Medical Center,2 Gladstone Institute of Virology and Immunology,4 Department of Pathology,5 Liver Center, University of California, San Francisco, California6

Received 18 February 2004/ Accepted 18 March 2004

The hepatitis C virus (HCV) core protein represents the first 191 amino acids of the viral precursor polyprotein and is cotranslationally inserted into the membrane of the endoplasmic reticulum (ER). Processing at position 179 by a recently identified intramembrane signal peptide peptidase leads to the generation and potential cytosolic release of a 179-amino-acid matured form of the core protein. Using confocal microscopy, we observed that a fraction of the mature core protein colocalized with mitochondrial markers in core-expressing HeLa cells and in Huh-7 cells containing the full-length HCV replicon. Subcellular fractionation confirmed this observation and showed that the core protein associates with purified mitochondrial fractions devoid of ER contaminants. The core protein also fractionated with mitochondrion-associated membranes, a site of physical contact between the ER and mitochondria. Using immunoelectron microscopy and in vitro mitochondrial import assays, we showed that the core protein is located on the mitochondrial outer membrane. A stretch of 10 amino acids within the hydrophobic C terminus of the processed core protein conferred mitochondrial localization when it was fused to green fluorescent protein. The location of the core protein in the outer mitochondrial membrane suggests that it could modulate apoptosis or lipid transfer, both of which are associated with this subcellular compartment, during HCV infection.

* Corresponding author. Mailing address: Gladstone Institute of Virology and Immunology, University of California, P.O. Box 419100, San Francisco, CA 94141-9100. Phone: (415) 695-3794. Fax: (415) 695-1364. E-mail: mott{at}gladstone.ucsf.edu.

{ddagger} This paper is dedicated to Harald zur Hausen on the occasion of his retirement as scientific director of the German Cancer Research Center and for his support, mentoring, and motivation.

{dagger} T.P. and J.K. contributed equally to this study.

Journal of Virology, August 2004, p. 7958-7968, Vol. 78, No. 15
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.15.7958-7968.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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