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Journal of Virology, February 2006, p. 1915-1921, Vol. 80, No. 4
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.4.1915-1921.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Core Protein of Pestiviruses Is Processed at the C Terminus by Signal Peptide Peptidase

Manuela Heimann,1 Gleyder Roman Sosa,1 Bruno Martoglio,2 Heinz-Jürgen Thiel,1 and Till Rümenapf1*

Institut für Virologie (FB Veterinärmedizin), Justus Liebig Universität Giessen, Frankfurter Str. 107, D-35392 Giessen, Germany,1 Novartis Institutes for BioMedical Research, Novartis Pharma AG, CH-4002 Basel, Switzerland2

Received 10 September 2005/ Accepted 18 November 2005

The core protein of pestiviruses is released from the polyprotein by viral and cellular proteinases. Here we report on an additional intramembrane proteolytic step that generates the C terminus of the core protein. C-terminal processing of the core protein of classical swine fever virus (CSFV) was blocked by the inhibitor (Z-LL)2-ketone, which is specific for signal peptide peptidase (SPP). The same effect was obtained by overexpression of the dominant-negative SPP D265A mutant. The presence of (Z-LL)2-ketone reduced the viability of CSFV almost 100-fold in a concentration-dependent manner. Reduction of virus viability was also observed in infection experiments using a cell line that inducibly expressed SPP D265A. The position of SPP cleavage was determined by C-terminal sequencing of core protein purified from virions. The C terminus of CSFV core protein is alanine255 and is located in the hydrophobic center of the signal peptide. The intramembrane generation of the C terminus of the CSFV core protein is almost identical to the processing scheme of the core protein of hepatitis C viruses.

* Corresponding author. Mailing address: Institut für Virologie, FB Veterinärmedizin, Justus Liebig Universität Giessen, Frankfurter Str. 107, D-35392 Giessen, Germany. Phone: 49-641-9938356. Fax: 49-641-9938359. E-mail: Till.H.Ruemenapf{at}vetmed.uni-giessen.de.

Journal of Virology, February 2006, p. 1915-1921, Vol. 80, No. 4
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.4.1915-1921.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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