Abstract
The presence of cellular protein coding sequences within viral RNA genomes is a unique and particularly interesting feature of cytopathogenic (cp) pestiviruses. Here we report the identification and characterization of two novel cellular sequences in the genomes of cp bovine viral diarrhea virus (BVDV) strains. In BVDV strain CP X604, we detected a duplication of the genomic region encoding NS3, NS4A, and part of NS4B, together with an insertion of sequences that code for cellular gamma-aminobutyric acid (A) receptor-associated protein [GABA(A)-RAP]. Transient-expression studies showed that the GABA(A)-RAP sequence leads to additional processing of the viral polyprotein and thereby to the expression of nonstructural protein NS3. Transfection of bovine cells with RNA transcribed from an infectious cDNA clone revealed that the GABA(A)-RAP-encoding insertion together with the duplicated viral sequences constitutes the genetic basis for the cytopathogenicity of strain CP X604. Surprisingly, molecular analysis of another cp BVDV strain (CP 721) resulted in the identification of a cellular Golgi-associated ATPase enhancer of 16 kDa (GATE-16)-encoding insertion together with duplicated viral sequences. To our knowledge, the genomes of CP X604 and CP 721 are the first viral RNAs found with cellular sequences encoding GABA(A)-RAP and GATE-16, respectively. Interestingly, the two cellular proteins belong to a family of eukaryotic proteins involved in various intracellular trafficking processes. Processing after the C-terminal glycine residue of GABA(A)-RAP and GATE-16 by cellular proteases is essential for covalent attachment to target molecules. Accordingly, it can be assumed that these cellular proteases also recognize the cleavage sites in the context of the respective viral polyproteins and thereby lead to the generation of NS3, the marker protein of cp BVDV.
Highlights
The genus Pestivirus within the family Flaviviridae comprises the species Bovine viral diarrhea virus 1 (BVDV-1), bovine viral diarrhea virus (BVDV)-2, Classical swine fever virus, and Border disease virus [10, 17]
The pestivirus genome consists of a positive-stranded nonpolyadenylated RNA molecule with a size of approximately 12.3 kb which contains one large open reading frame (ORF) flanked by 5Ј and 3Ј nontranslated regions (NTR)
One important difference between cp and noncp BVDV is the expression of NS3, which is colinear to the C-terminal part of NS2-3
Summary
The genus Pestivirus within the family Flaviviridae comprises the species Bovine viral diarrhea virus 1 (BVDV-1), BVDV-2, Classical swine fever virus, and Border disease virus [10, 17]. This is the first report about the presence of a cellular GABA(A)-RAP coding sequence within a viral genome. This result strongly supports the assumption that the cellular insertion identified in the genome of CP X604 was derived from a bovine mRNA encoding GABA(A)-RAP.
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