This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lackner, T.
Right arrow Articles by Tautz, N.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lackner, T.
Right arrow Articles by Tautz, N.

 Previous Article  |  Next Article 

Journal of Virology, October 2004, p. 10765-10775, Vol. 78, No. 19
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.19.10765-10775.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Temporal Modulation of an Autoprotease Is Crucial for Replication and Pathogenicity of an RNA Virus

T. Lackner,1 A. Müller,1 A. Pankraz,1 P. Becher,1 H.-J. Thiel,1 A. E. Gorbalenya,2* and N. Tautz1*

Institut für Virologie (Fachbereich Veterinärmedizin), Justus-Liebig-Universität Giessen, Giessen, Germany,1 Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands2

Received 9 March 2004/ Accepted 24 May 2004

Pestiviruses belong to the family Flaviviridae, and their genome is a single-stranded RNA of positive polarity encoding one large polyprotein which is further processed into mature proteins. Noncytopathogenic (noncp) strains of the pestivirus bovine viral diarrhea virus (BVDV) can establish persistent infection. In persistently infected animals, noncp BVDVs occasionally acquire mutations in viral nonstructural protein 2 (NS2) that give rise to cytopathogenic (cp) BVDV variants, and, eventually, lead to the onset of lethal disease. A molecular marker of cp BVDV infection is a high-level expression of the replicative NS3 protease/helicase that together with NS2 is derived from NS2-3. Here, we present evidence for NS2-3 autoprocessing by a newly identified cysteine protease in NS2 that is distantly related to the NS2-3 autoprotease of hepatitis C and GB viruses. The vital role of this autoprotease in BVDV infection was established, implying an essential function for NS3 in pestiviral RNA replication which cannot be supplied by its NS2-3 precursor. Accordingly, and contrary to a current paradigm, we detected almost complete cleavage of NS2-3 in noncp BVDV at early hours of infection. At 6 to 9 h postinfection, NS2-3 autoprocessing diminished to barely detectable levels for noncp BVDV but decreased only moderately for cp BVDV. Viral RNA synthesis rates strictly correlated with different NS3 levels in noncp and cp BVDV-infected cells, implicating the NS2 autoprotease in RNA replication control. The biotype-specific modulation of NS2-3 autoprocessing indicates a crucial role of the NS2 autoprotease in the pathogenicity of BVDV.

* Corresponding author. Mailing address for N. Tautz: Institut für Virologie (FB Veterinärmedizin), Justus-Liebig-Universität Giessen, Frankfurter Strasse 107, 35392 Giessen, Germany. Phone: 49 641 99 3 83 94. Fax: 49 641 99 3 83 59. E-mail: Norbert.Tautz{at}vetmed.uni-giessen.de. Mailing address for A.E. Gorbalenya: Department of Medical Microbiology, Leiden University Medical Center, Room L4-34, Albinusdreef 2, P.O. Box 9600, 2300 RC Leiden, The Netherlands. Phone: 31 71 5 26 16 52. Fax: 31 71 5 26 67 61. E-mail: a.e.gorbalenya{at}lumc.nl.

Journal of Virology, October 2004, p. 10765-10775, Vol. 78, No. 19
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.19.10765-10775.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Pankraz, A., Preis, S., Thiel, H.-J., Gallei, A., Becher, P. (2009). A Single Point Mutation in Nonstructural Protein NS2 of Bovine Viral Diarrhea Virus Results in Temperature-Sensitive Attenuation of Viral Cytopathogenicity. J. Virol. 83: 12415-12423 [Abstract] [Full Text]  
  • Tews, B. A., Schurmann, E.-M., Meyers, G. (2009). Mutation of Cysteine 171 of Pestivirus Erns RNase Prevents Homodimer Formation and Leads to Attenuation of Classical Swine Fever Virus. J. Virol. 83: 4823-4834 [Abstract] [Full Text]  
  • Yamane, D., Zahoor, M. A., Mohamed, Y. M., Azab, W., Kato, K., Tohya, Y., Akashi, H. (2009). Inhibition of Sphingosine Kinase by Bovine Viral Diarrhea Virus NS3 Is Crucial for Efficient Viral Replication and Cytopathogenesis. J. Biol. Chem. 284: 13648-13659 [Abstract] [Full Text]  
  • Welbourn, S., Jirasko, V., Breton, V., Reiss, S., Penin, F., Bartenschlager, R., Pause, A. (2009). Investigation of a role for lysine residues in non-structural proteins 2 and 2/3 of the hepatitis C virus for their degradation and virus assembly. J. Gen. Virol. 90: 1071-1080 [Abstract] [Full Text]  
  • Schregel, V., Jacobi, S., Penin, F., Tautz, N. (2009). Hepatitis C virus NS2 is a protease stimulated by cofactor domains in NS3. Proc. Natl. Acad. Sci. USA 106: 5342-5347 [Abstract] [Full Text]  
  • Gallei, A., Blome, S., Gilgenbach, S., Tautz, N., Moennig, V., Becher, P. (2008). Cytopathogenicity of Classical Swine Fever Virus Correlates with Attenuation in the Natural Host. J. Virol. 82: 9717-9729 [Abstract] [Full Text]  
  • Tscherne, D. M., Evans, M. J., MacDonald, M. R., Rice, C. M. (2008). Transdominant Inhibition of Bovine Viral Diarrhea Virus Entry. J. Virol. 82: 2427-2436 [Abstract] [Full Text]  
  • Murray, C. L., Marcotrigiano, J., Rice, C. M. (2008). Bovine Viral Diarrhea Virus Core Is an Intrinsically Disordered Protein That Binds RNA. J. Virol. 82: 1294-1304 [Abstract] [Full Text]  
  • Slobodskaya, O., Laarman, A., Spaan, W. J. M. (2008). Intracellular Restriction of a Productive Noncytopathic Coronavirus Infection. J. Virol. 82: 451-460 [Abstract] [Full Text]  
  • Tews, B. A., Meyers, G. (2007). The Pestivirus Glycoprotein Erns Is Anchored in Plane in the Membrane via an Amphipathic Helix. J. Biol. Chem. 282: 32730-32741 [Abstract] [Full Text]  
  • Meyers, G., Ege, A., Fetzer, C., von Freyburg, M., Elbers, K., Carr, V., Prentice, H., Charleston, B., Schurmann, E.-M. (2007). Bovine Viral Diarrhea Virus: Prevention of Persistent Fetal Infection by a Combination of Two Mutations Affecting Erns RNase and Npro Protease. J. Virol. 81: 3327-3338 [Abstract] [Full Text]  
  • Yamane, D., Kato, K., Tohya, Y., Akashi, H. (2006). The double-stranded RNA-induced apoptosis pathway is involved in the cytopathogenicity of cytopathogenic Bovine viral diarrhea virus.. J. Gen. Virol. 87: 2961-2970 [Abstract] [Full Text]  
  • Tellinghuisen, T. L., Paulson, M. S., Rice, C. M. (2006). The NS5A Protein of Bovine Viral Diarrhea Virus Contains an Essential Zinc-Binding Site Similar to That of the Hepatitis C Virus NS5A Protein.. J. Virol. 80: 7450-7458 [Abstract] [Full Text]  
  • Schweizer, M., Matzener, P., Pfaffen, G., Stalder, H., Peterhans, E. (2006). "Self" and "Nonself" Manipulation of Interferon Defense during Persistent Infection: Bovine Viral Diarrhea Virus Resists Alpha/Beta Interferon without Blocking Antiviral Activity against Unrelated Viruses Replicating in Its Host Cells. J. Virol. 80: 6926-6935 [Abstract] [Full Text]  
  • Lackner, T., Thiel, H.-J., Tautz, N. (2006). Dissection of a viral autoprotease elucidates a function of a cellular chaperone in proteolysis. Proc. Natl. Acad. Sci. USA 103: 1510-1515 [Abstract] [Full Text]  
  • Gil, L. H. V. G., Ansari, I. H., Vassilev, V., Liang, D., Lai, V. C. H., Zhong, W., Hong, Z., Dubovi, E. J., Donis, R. O. (2006). The Amino-Terminal Domain of Bovine Viral Diarrhea Virus Npro Protein Is Necessary for Alpha/Beta Interferon Antagonism. J. Virol. 80: 900-911 [Abstract] [Full Text]  
  • Gallei, A., Orlich, M., Thiel, H.-J., Becher, P. (2005). Noncytopathogenic Pestivirus Strains Generated by Nonhomologous RNA Recombination: Alterations in the NS4A/NS4B Coding Region. J. Virol. 79: 14261-14270 [Abstract] [Full Text]  
  • Fetzer, C., Tews, B. A., Meyers, G. (2005). The Carboxy-Terminal Sequence of the Pestivirus Glycoprotein Erns Represents an Unusual Type of Membrane Anchor. J. Virol. 79: 11901-11913 [Abstract] [Full Text]  
  • Welbourn, S., Green, R., Gamache, I., Dandache, S., Lohmann, V., Bartenschlager, R., Meerovitch, K., Pause, A. (2005). Hepatitis C Virus NS2/3 Processing Is Required for NS3 Stability and Viral RNA Replication. J. Biol. Chem. 280: 29604-29611 [Abstract] [Full Text]  
  • Lackner, T., Muller, A., Konig, M., Thiel, H.-J., Tautz, N. (2005). Persistence of Bovine Viral Diarrhea Virus Is Determined by a Cellular Cofactor of a Viral Autoprotease. J. Virol. 79: 9746-9755 [Abstract] [Full Text]  
  • Pankraz, A., Thiel, H.-J., Becher, P. (2005). Essential and Nonessential Elements in the 3' Nontranslated Region of Bovine Viral Diarrhea Virus. J. Virol. 79: 9119-9127 [Abstract] [Full Text]  
  • Gallei, A., Rumenapf, T., Thiel, H.-J., Becher, P. (2005). Characterization of Helper Virus-Independent Cytopathogenic Classical Swine Fever Virus Generated by an In Vivo RNA Recombination System. J. Virol. 79: 2440-2448 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»