Temporal modulation of an autoprotease is crucial for replication and pathogenicity of an RNA virus
| Autor: | T. Lackner, Alexander Pankraz, Heinz-Jürgen Thiel, Norbert Tautz, Alexander E. Gorbalenya, Paul Becher, A. Müller |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
Viral nonstructural protein
viruses Immunology Molecular Sequence Data Mutation Missense Sequence Homology Replication GB virus C Hepacivirus Viral Nonstructural Proteins Virus Replication Microbiology Virus GB virus B Cell Line GB virus A Viral Proteins Cytopathogenic Effect Viral Virology Cricetinae Animals Amino Acid Sequence NS3 Binding Sites Diarrhea Viruses Bovine Viral biology Pestivirus RNA virus diseases RNA virus biochemical phenomena metabolism and nutrition biology.organism_classification Cysteine Endopeptidases Viral replication Amino Acid Substitution Insect Science RNA Viral Cattle RNA Helicases Peptide Hydrolases |
| Zdroj: | Journal of virology. 78(19) |
| ISSN: | 0022-538X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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