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Bovine ephemeral fever rhabdovirus ?1 protein has viroporin-like properties and binds importin ?1 and importin 7.

ABSTRACT: Bovine ephemeral fever virus (BEFV) is an arthropod-borne rhabdovirus that is classified as the type species of the genus Ephemerovirus. In addition to the five canonical rhabdovirus structural proteins (N, P, M, G, and L), the large and complex BEFV genome contains several open reading frames (ORFs) between the G and L genes (?1, ?2/?3, ?, and ?) encoding proteins of unknown function. We show that the 10.5-kDa BEFV ?1 protein is expressed in infected cells and, consistent with previous predictions based on its structure, has the properties of a viroporin. Expression of a BEFV ?1-maltose binding protein (MBP) fusion protein in Escherichia coli was observed to inhibit cell growth and increase membrane permeability to hygromycin B. Increased membrane permeability was also observed in BEFV-infected mammalian cells (but not cells infected with an ?1-deficient BEFV strain) and in cells expressing a BEFV ?1-green fluorescent protein (GFP) fusion protein, which was shown by confocal microscopy to localize to the Golgi complex. Furthermore, the predicted C-terminal cytoplasmic domain of ?1, which contains a strong nuclear localization signal (NLS), was translocated to the nucleus when expressed independently, and in an affinity chromatography assay employing a GFP trap, the full-length ?1 was observed to interact specifically with importin ?1 and importin 7 but not with importin ?3. These data suggest that, in addition to its function as a viroporin, BEFV ?1 may modulate components of nuclear trafficking pathways, but the specific role thereof remains unclear. Although rhabdovirus accessory genes occur commonly among arthropod-borne rhabdoviruses, little is known of their functions. Here, we demonstrate that the BEFV ?1 ORF encodes a protein which has the structural and functional characteristics of a viroporin. We show that ?1 localizes in the Golgi complex and increases cellular permeability. We also show that BEFV ?1 binds importin ?1 and importin 7, suggesting that it may have a yet unknown role in modulating nuclear trafficking. This is the first functional analysis of an ephemerovirus accessory protein and of a rhabdovirus viroporin.

SUBMITTER: Joubert DA

PROVIDER: S-EPMC3911578 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Bovine ephemeral fever rhabdovirus α1 protein has viroporin-like properties and binds importin β1 and importin 7.

Joubert D Albert DA Blasdell Kim R KR Audsley Michelle D MD Trinidad Lee L Monaghan Paul P Dave Keyur A KA Lieu Kim G KG Amos-Ritchie Rachel R Jans David A DA Moseley Gregory W GW Gorman Jeffrey J JJ Walker Peter J PJ

Journal of virology 20131120 3

Bovine ephemeral fever virus (BEFV) is an arthropod-borne rhabdovirus that is classified as the type species of the genus Ephemerovirus. In addition to the five canonical rhabdovirus structural proteins (N, P, M, G, and L), the large and complex BEFV genome contains several open reading frames (ORFs) between the G and L genes (α1, α2/α3, β, and γ) encoding proteins of unknown function. We show that the 10.5-kDa BEFV α1 protein is expressed in infected cells and, consistent with previous predicti ...[more]

PMID: 24257609

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Project description:Bovine ephemeral fever virus (BEFV) is an arthropod-borne rhabdovirus that causes a debilitating disease of cattle in Africa, Asia, and Australia; however, its global geodynamics are poorly understood. An evolutionary analysis of G gene (envelope glycoprotein) ectodomain sequences of 97 BEFV isolates collected from Australia during 1956 to 2012 revealed that all have a single common ancestor and are phylogenetically distinct from BEFV sampled in other geographical regions. The age of the Australian clade is estimated to be between 56 and 65 years, suggesting that BEFV has entered the continent on few occasions since it was first reported in 1936 and that the 1955-1956 epizootic was the source of all currently circulating viruses. Notably, the Australian clade has evolved as a single genetic lineage across the continent and at a high evolutionary rate of ∼10(-3) nucleotide substitutions/site/year. Screening of 66 isolates using monoclonal antibodies indicated that neutralizing antigenic sites G1, G2, and G4 have been relatively stable, although variations in site G3a/b defined four antigenic subtypes. A shift in an epitope at site G3a, which occurred in the mid-1970s, was strongly associated with a K218R substitution. Similarly, a shift at site G3b was associated primarily with substitutions at residues 215, 220, and 223, which map to the tip of the spike on the prefusion form of the G protein. Finally, we propose that positive selection on residue 215 was due to cross-reacting neutralizing antibody to Kimberley virus (KIMV). This is the first study of the evolution of BEFV in Australia, showing that the virus has entered the continent only once during the past 50 to 60 years, it is evolving at a relatively constant rate as a single genetic lineage, and although the virus is relatively stable antigenically, mutations have resulted in four antigenic subtypes. Furthermore, the study shows that the evolution of BEFV in Australia appears to be driven, at least in part, by cross-reactive antibodies to KIMV which has a similar distribution and ecology but has not been associated with disease. As BEFV and KIMV are each known to be present in Africa and Asia, this interaction may occur on a broader geographic scale.

Dataset Information

Bovine ephemeral fever rhabdovirus ?1 protein has viroporin-like properties and binds importin ?1 and importin 7.

Publications

Bovine ephemeral fever rhabdovirus α1 protein has viroporin-like properties and binds importin β1 and importin 7.

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