Members of the Paramyxovirinae subfamily include viruses such as measles, mumps, parainfluenza viruses (PIV) of humans, Newcastle Disease virus of birds, Sendai virus (SeV) of rodents, and simian virus 5 (SV5), which has been isolated from monkeys, dogs, pigs, and humans. Paramyxoviruses also have zoonotic potential, as has been observed with the newly emergent Hendra (HeV) and Nipah viruses, which naturally infect fruit bats but can cause serious, often fatal infections when transmitted to farm and domestic animals and to humans (reviewed in ref.2). Like all viruses, upon infection of cells, paramyxoviruses are subjected to a variety of intracellular antiviral responses, including the IFN response (reviewed in refs. 3-5). Over the last few years, it has become clear that protein products of the P͞V͞C gene of viruses within the Paramyxovirinae subfamily (for review of the molecular biology of paramyxoviruses, see ref. 1) specifically reduce the effectiveness of the IFN response. For example, the V protein of SV5 targets signal transducer and activator of transcription 1 (STAT1) for degradation, thereby blocking both IFN-␣͞ and IFN-␥ signaling within infected cells (6), whereas the C proteins of SeV block IFN signaling by interfering with STAT phosphorylation or stability (reviewed in refs. 7-9). As well as blocking IFN signaling, these viruses also specifically limit the production of IFN by virus-infected cells (10-12). The block on IFN- production is at the level of transcription, because very little IFN- mRNA is induced in cells infected with SV5. In contrast, large amounts of IFN- mRNA (and thus IFN-) are produced by cells infected with a recombinant of SV5 (SV5V⌬C) that produces a truncated V protein lacking the cysteine-rich C terminus (which is dispensable for virus replication), suggesting that the V protein is responsible for the block on IFN production. This conclusion is supported by the observation that in gene reporter assays, the V proteins of SV5, PIV2, and SeV inhibit the activation of the IFN- promoter in response to intracellular dsRNA (11).Initial transcription from the IFN- promoter requires the activation of a number of cellular transcription factors, including IFN regulatory factor (IRF)-3 and NF-B, leading to the formation of an enhanceosome complex that associates with the basal transcriptional machinery to recruit RNA polymerase II to the IFN- promoter (reviewed in refs. 3 and 13). The molecular details of how the V proteins of paramyxoviruses block IFN production are not known, but the block affects the signal transduction pathway that activates both NF-B and IRF-3 in response to dsRNA. Thus, these transcription factors are not activated in cells infected with wild-type SV5 but are activated in cells infected with SV5V⌬C. Furthermore, ectopic expression of SV5 V inhibits the activation of IRF-3 and NF-B by both dsRNA and infection with SV5V⌬C (10, 11). Unlike the targeted degradation of signal transducer and activator of transcription 1 (STAT1), which requires both the N-and C-t...
The induction of IFN-beta by the paramyxovirus PIV5 (formerly known as SV5) is limited by the action of the viral V protein that targets the cellular RNA helicase mda-5. Here we show that 12 other paramyxoviruses also target mda-5 by a direct interaction between the conserved cysteine-rich C-terminus of their V proteins and the helicase domain of mda-5. The inhibition of IFN-beta induction is not species-restricted, being observed in a range of mammalian cells as well as in avian cells, and we show that the inhibition of mda-5 function is also not restricted to mammalian cells. In contrast, the V proteins do not bind to the related RNA helicase RIG-I and do not inhibit its activity. The relative contributions of mda-5 and RIG-I to IFN-beta induction are discussed.
We have identified two novel proteins that interact specifically with the C-terminal repression domain of Interferon Regulatory Factor-2 (IRF-2). These proteins, which we term IRF-2 binding proteins 1 and 2 (IRF-2BP1 and IRF-2BP2, the latter having two splicing isoforms, A and B), are nuclear proteins, and have the properties of IRF-2-dependent transcriptional co-repressors that can inhibit both enhancer-activated and basal transcription in a manner that is not dependent upon histone deacetylation. IRF-2BP1 and IRF-2BP2A/B contain an N-terminal zinc finger and a C-terminal RING finger domain of the C3HC4 subclass, but show no homology to other known transcriptional regulators; they therefore define a new family of co- repressor proteins. An alternatively spliced form of IRF-2 that lacks two amino acids (valines 177 and 178) in the central portion of the protein (IRF-2[S]) cannot bind to these co-repressors and cannot mediate repression despite having the same C- terminal repression domain as IRF-2, suggesting that the relative conformation of the DNA binding domain and the C-terminal region of IRF-2 is crucial for transcriptional repression.
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