Insertion of a bovine SMT3B gene in NS4B and duplication of NS3 in a bovine viral diarrhea virus genome correlate with the cytopathogenicity of the virus

Qi, Fengxia; Ridpath, Julia F.; Berry, Eugene S.

doi:10.1016/s0168-1702(98)00073-2

Cited by 49 publications

(29 citation statements)

References 31 publications

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“…Data were analyzed as described in the legend to Fig. 4B. have been cloned from eukaryotes as diverse as yeast, Arabidopsis, and humans (16,35,40,41). These proteins in general display greater than 50% identity with one another but also roughly 20% identity with ubiquitin.…”

Section: Discussionmentioning

confidence: 99%

A Functional Interaction between Dorsal and Components of the Smt3 Conjugation Machinery

Bhaskar

Valentine²,

Courey

2000

Journal of Biological Chemistry

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To identify proteins that regulate the function of Dorsal, a Drosophila Rel family transcription factor, we employed a yeast two-hybrid screen to search for genes encoding Dorsal-interacting proteins. Six genes were identified, including two that encode previously known Dorsal-interacting proteins (Twist and Cactus), three that encode novel proteins, and one that encodes Drosophila Ubc9 (DmUbc9), a protein thought to conjugate the ubiquitin-like polypeptide Smt3 to protein substrates. We have found that DmUbc9 binds and conjugates Drosophila Smt3 (DmSmt3) to Dorsal. In cultured cells, DmUbc9 was found to relieve inhibition of Dorsal nuclear uptake by Cactus, allowing Dorsal to enter the nucleus and activate transcription. The effect of DmUbc9 on Dorsal activity was potentiated by the overexpression of DmSmt3. We have also identified a DmSmt3-activating enzyme, DmSAE1/DmSAE2 and found that it further potentiates Dorsal-mediated activation.Dorsoventral patterning of the Drosophila embryo is initiated by Dorsal, a member of the Rel family of transcription factors. This maternally expressed factor is distributed in a nuclear concentration gradient in the blastoderm embryo (1) and functions as an activator and repressor of transcription to establish multiple domains of zygotic gene activity, thereby subdividing the embryo into several discrete domain along its dorsoventral axis (2, 3). Dorsal-binding proteins direct the spatially regulated nuclear import of Dorsal via an evolutionarily conserved signal transduction pathway, which targets Dorsal and its cytoplasmic inhibitor Cactus (4 -6). Prior to activation of the pathway, an interaction between Cactus and Dorsal serves to retain Dorsal in the cytoplasm. Activation of the pathway by a signal originating in the ventral extraembryonic space results in phosphorylation of Cactus and Dorsal. The phosphorylation of Cactus triggers its degradation via the ubiquitin-proteasome pathway, freeing Dorsal to enter the nucleus (7), whereas the phosphorylation of Dorsal is required to render the factor competent for efficient nuclear uptake (8).A very similar pathway involving the vertebrate homolog of Cactus, IB is involved in the regulated nuclear import of vertebrate Rel family proteins, such as NFB (9, 10). In addition, recent studies suggest that the nuclear import of NFB may be influenced by the Smt3 conjugation pathway (11). Smt3 is a small ubiquitin-like protein that can be enzymatically conjugated to various protein substrates via an amide linkage between the C-terminal carboxyl group of Smt3 and a lysine ⑀-amino group on the target protein. Conjugation of mammalian SMT3C to IB is thought to stabilize IB by blocking ubiquitylation and therefore subsequent proteasomal degradation. By stabilizing IB, the vertebrate Smt3 conjugation pathway results in the down-regulation of NFB activity.In an effort to illuminate further the mechanisms by which Dorsal activity is regulated, we sought to identify novel Dorsal interacting proteins via a yeast two-hybrid screen. One of the prot...

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Section: Discussionmentioning

confidence: 99%

A Functional Interaction between Dorsal and Components of the Smt3 Conjugation Machinery

Bhaskar

Valentine²,

Courey

2000

Journal of Biological Chemistry

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“…Noncytopathic BVDV code for an NS2-3 protein that in cytopathic BVDV is processed to an NS3 protein (5). Processing of the NS2-3 protein in cytopathic BVDV1 occurs by several different strategies depending on the viral strain (3,9,10,13,15,20,21,27,28). Most commonly it is associated with the insertion of sequences into the viral genome.…”

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confidence: 99%

“…In BVDV1, the amino acid sequences flanking the carboxy-terminal end of inserted sequences correspond to either amino acid position 1535 or position 1589 (numbering is based on BVDV-1 strain SD-1, GenBank accession number M96751), referred to as positions A and B, respectively (13). Most reported insertions into BVDV1 have been at position B and consist of duplicated viral genomic sequences and/or ubiquitin coding sequences (8,21), although insertions of other cellular coding sequences have been reported (2,13,20). In contrast, limited information is available on the molecular characterization of cytopathic BVDV2 insertions.…”

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confidence: 99%

Detection and Characterization of Genetic Recombination in Cytopathic Type 2 Bovine Viral Diarrhea Viruses

Ridpath

Neill

2000

J Virol

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“…For the closely related BVDV, isolation of CP G1-like field isolates carrying duplicated viral sequences together with insertions of cellular mRNA sequences has frequently been reported (4,9,12,21,32,34,41). In contrast, CSFV field strains with duplications and/or insertions of cellular sequences have not been described so far.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Helper Virus-Independent Cytopathogenic Classical Swine Fever Virus Generated by an In Vivo RNA Recombination System

Gallei

Rümenapf

Thiel

et al. 2005

J Virol

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Molecular analyses revealed that most cytopathogenic (cp) pestivirus strains evolve from noncytopathogenic (noncp) viruses by nonhomologous RNA recombination. In contrast to bovine viral diarrhea virus (BVDV), cp classical swine fever virus (CSFV) field isolates were rarely detected and always represented helper virusdependent subgenomes. To investigate RNA recombination in more detail, we recently established an in vivo system allowing the efficient generation of recombinant cp BVDV strains in cell culture after transfecting a synthetic subgenomic and nonreplicatable transcript into cells being infected with noncp BVDV (A. Gallei, A. Pankraz, H.-J. Thiel, and P. Becher, J. Virol. 78:6271-6281, 2004). Using an analogous approach, the first helper virus-independent cp CSFV strain (CP G1) has now been generated by RNA recombination. Accordingly, this study demonstrates the applicability of RNA recombination for designing new viral RNA genomes. The genomic RNA of CP G1 has a calculated size of 18.139 kb, almost 6 kb larger than all previously described CSFV genomes. It contains cellular sequences encoding a polyubiquitin fragment directly upstream of the nonstructural protein NS3 coding gene together with a duplication of viral sequences. CP G1 induces a cytopathic effect on different tissue culture cell lines from pigs and cattle. Subsequent analyses addressed growth kinetics, expression of NS3, and genetic stability of CP G1.Classical swine fever virus (CSFV), the causative agent of an economically important disease in pigs, forms together with the species Bovine viral diarrhea virus 1 (BVDV-1), BVDV-2, and Border disease virus (BDV) the genus Pestivirus, family Flaviviridae (11,22). Highly virulent CSFV strains can cause a severe form of classical swine fever, characterized by pyrexia; hemorrhages in the skin, mucosa, and inner organs; anorexia; diarrhea; and, in late stages, central nervous disorders resulting in high morbidity and mortality (48). However, most CSFV strains isolated from recent outbreaks in Europe led to chronic forms of disease with less characteristic symptoms (16).Pestiviruses are small enveloped viruses encompassing a single-stranded RNA genome of positive polarity with a length of about 12.3 kb. The viral genomic RNA is neither capped nor polyadenylated and contains one large open reading frame (ORF) flanked by 5Ј and 3Ј nontranslated regions (NTR); the latter harbor cis-active elements essential for viral translation and replication. The ORF encodes a polyprotein of approximately 3,900 amino acids (aa) that is co-and posttranslationally processed by cellular and viral proteases to the mature viral proteins (22,29,36,48).For pestiviruses, cytopathogenic (cp) and noncytopathogenic (noncp) strains are distinguished by their ability to cause a cytopathic effect (CPE) in susceptible tissue culture cells (18,28). For BVDV it is well documented that cp strains mostly evolve by nonhomologous RNA recombination in animals persistently infected with noncp BVDV. The emergence of cp BVDV in persistent...

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Insertion of a bovine SMT3B gene in NS4B and duplication of NS3 in a bovine viral diarrhea virus genome correlate with the cytopathogenicity of the virus

Cited by 49 publications

References 31 publications

A Functional Interaction between Dorsal and Components of the Smt3 Conjugation Machinery

A Functional Interaction between Dorsal and Components of the Smt3 Conjugation Machinery

Detection and Characterization of Genetic Recombination in Cytopathic Type 2 Bovine Viral Diarrhea Viruses

Characterization of Helper Virus-Independent Cytopathogenic Classical Swine Fever Virus Generated by an In Vivo RNA Recombination System

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