An open reading frame (ORF) overlapping the amino-terminal portion of the Sendai virus (SeV)PSendai virus (SeV) is an enveloped virus with a linear, nonsegmented, negative-sense RNA genome of 15,384 nucleotides and belongs to the genus Respirovirus of the family Paramyxoviridae. The genome encodes, in 3Ј-to-5Ј order, the nucleocapsid (N) protein, phospho (P) protein, matrix (M) protein, fusion (F) protein, hemagglutinin-neuraminidase (HA), and large (L) protein. Gene expression is usually monocistronic, generating a single mRNA which primarily directs a single translation product. However, P gene expression is exceptional because it gives rise to multiple protein species by a process known as RNA editing and by the use of an overlapping open reading frame (ORF), as shown in Fig. 1 (for a review, see reference 27).In RNA editing, one nontemplated G residue is cotranscriptionally inserted at a specific position to generate the edited mRNA that encodes the protein termed V (43). The unedited mRNA that is the exact copy of the P gene encodes the P protein, the smaller subunit of RNA polymerase. The P and V proteins are therefore amino coterminal, while the Ϫ1 frame is used to generate the carboxyl-terminal half of the V protein (27). The V unique carboxyl-terminal region contains seven cysteine residues. These cysteine residues are highly conserved in paramyxovirus V proteins, form zinc finger motifs, and indeed bind Zn 2ϩ (17,33). To study the role of SeV V protein, we generated a series of V knockout viruses by reverse genetics and demonstrated that the V protein is completely dispensable for viral replication in tissue culture cells and devotes itself to maintaining high viral loads and causing severe pneumonia in mice (20). This luxury function required for in vivo pathogenesis was mapped to the V unique carboxyl-terminal portion (21) and associated with its zinc binding capacity (17).An ORF overlapping the amino-terminal portion of the SeV P ORF in the ϩ1 frame produces a nested set of carboxycoterminal proteins called CЈ, C, Y1, and Y2 and referred to collectively as the C proteins.
Earlier studies demonstrated the induction of beta 2-interferon (IFN-beta 2) in human diploid fibroblasts (FS-4 strain) exposed to tumor necrosis factor (TNF). These studies suggested that IFN-beta 2 mediates an antiviral effect in TNF-treated cells and exerts a feedback inhibition of the mitogenic effect of TNF. Here we demonstrate that the expression of the antiviral action of TNF can be enhanced by prior exposure of FS-4 cells to trace amounts of IFN-beta 1. IFN-beta 1, at a higher concentration, can directly increase the expression of IFN-beta 2. Exposure of cells to TNF enhanced IFN-beta 2 (but not IFN-beta 1) mRNA expression in response to poly(I).poly(C), an IFN inducer which is also known to stimulate FS-4 cell growth. Platelet-derived growth factor and interleukin-1 also led to the increased expression of IFN-beta 2. However, platelet-derived growth factor and interleukin-1 could override the antiviral effect of TNF and also that of exogenously added IFN-beta 1. Our data suggest that a complex network of interactions that involves the endogenous production of IFN-beta 2 is triggered by several growth-modulatory cytokines. Cellular homeostasis is likely to represent a balance between the induction of IFN-beta 2 by these cytokines and their ability to override the inhibitory actions of IFN-beta 2.
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