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J. Biol. Chem., Vol. 276, Issue 47, 44052-44063, November 23, 2001
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From the The hepatitis C virus (HCV)
RNA-dependent RNA polymerase (RdRp), represented by
nonstructural protein 5B (NS5B), is believed to form a
membrane-associated RNA replication complex together with other
nonstructural proteins and as yet unidentified host components.
However, the determinants for membrane association of this essential
viral enzyme have not been defined. By double label immunofluorescence
analyses, NS5B was found in the endoplasmic reticulum (ER) or an
ER-like modified compartment both when expressed alone or in the
context of the entire HCV polyprotein. The carboxyl-terminal 21 amino
acid residues were necessary and sufficient to target NS5B or a
heterologous protein to the cytosolic side of the ER membrane. This
hydrophobic domain is highly conserved among 269 HCV isolates analyzed
and predicted to form a transmembrane
Determinants for Membrane Association of the
Hepatitis C Virus RNA-dependent RNA Polymerase*
,,,, and
Department of Medicine II, University of
Freiburg, D-79106 Freiburg, Germany, the § Institut de
Biologie et Chimie des Protéines, CNRS-UMR 5086, F-69367,
Lyon Cedex 07, France, and the ¶ Center for the Study of
Hepatitis C, Rockefeller University, New York, New York 10021
-helix. Association of NS5B
with the ER membrane occurred by a posttranslational mechanism that was
ATP-independent. These features define the HCV RdRp as a new member of
the tail-anchored protein family, a class of integral membrane proteins
that are membrane-targeted posttranslationally via a carboxyl-terminal
insertion sequence. Formation of the HCV replication complex,
therefore, involves specific determinants for membrane association that
represent potential targets for antiviral intervention.
*
This work was supported by Grant Mo 799/1-2 from the
Deutsche Forschungsgemeinschaft (to D. M. and H. E. B.) and by
grants from the United States Public Health Service and the Greenberg Medical Research Foundation (to C. M. R.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Medicine
II, University Hospital Freiburg, Hugstetter Strasse 55, D-79106 Freiburg, Germany. Tel.: 49 761 270 3510; Fax: 49 761 270 3610; E-mail:
moradpou@ruf.uni-freiburg.de.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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