Interferon-Induced Alterations in the Pattern of Parainfluenza Virus 5 Transcription and Protein Synthesis and the Induction of Virus Inclusion Bodies

Carlos, T.S.; Fearns, Rachel; Randall, R. E.

doi:10.1128/jvi.79.22.14112-14121.2005

Cited by 30 publications

(35 citation statements)

References 36 publications

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“…In addition, viruses may also have subtle ways to use IFN responses to benefit their replication. For example, although V protein of parainfluenza 5 antagonizes IFN response by degrading STAT1, appropriate IFNs may change the pattern of viral transcription and protein synthesis, and thus facilitate the establishment of persistent infections (52)(53)(54). SM protein of EBV during the lytic cycle inhibits protein kinase R activation, whereas EBV LMP-1 protein can prime EBV latency cells for IFN production to establish the viral latency (55)(56)(57).…”

Section: Discussionmentioning

confidence: 99%

Human Bocavirus VP2 Upregulates IFN-β Pathway by Inhibiting Ring Finger Protein 125–Mediated Ubiquitination of Retinoic Acid–Inducible Gene-I

Luo

Zhang

Zheng

et al. 2013

The Journal of Immunology

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Precise regulation of innate immunity is crucial for maintaining optimal immune responses against infections. Whereas positive regulation of IFN signaling elicits rapid type I IFNs, negative regulation is equally important in preventing the production of superfluous IFNs that can be hazardous to the host. The positive regulators of IFN pathway are known to be the main targets of viruses to antagonize the innate immune system. Whether viruses target the negative regulators of IFN pathway remains to be fully investigated. In this study, we report that the structural protein VP2 of human Bocavirus modulates IFN pathway by targeting the ring finger protein 125 (RNF125), a negative regulator of type I IFN signaling, which conjugates Lys48-linked ubiquitination to retinoic acid–inducible gene-I (RIG-I) and subsequently leads to the proteasome-dependent degradation of RIG-I. VP2 not only upregulated Sendai virus (SeV)–induced IFNB promoter activity, but also enhanced SeV-induced IFN-β production at both mRNA and protein levels. In agreement, the level of Ser396-phosphorylated IFN regulatory factor 3 stimulated by SeV was enhanced in the presence of VP2. Furthermore, VP2 was demonstrated to physically interact with RNF125, resulting in the reduction of RNF125-mediated ubiquitination and proteasome-dependent degradation of RIG-I. Additional study indicated that endogenous RIG-I degradation was decreased in VP2-expressing cells. Our study delineates a unique phenomenon for aberrant activation of IFN regulatory factor 3 pathway and may represent a new mechanism underlying viral manipulation of the host immune system.

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Section: Discussionmentioning

confidence: 99%

Human Bocavirus VP2 Upregulates IFN-β Pathway by Inhibiting Ring Finger Protein 125–Mediated Ubiquitination of Retinoic Acid–Inducible Gene-I

Luo

Zhang

Zheng

et al. 2013

The Journal of Immunology

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“…The procedures for immunoblotting, immunofluorescence, and immunoprecipitation have been described previously (18,24). Antibodies used in these procedures included monoclonal antibodies against the PIV5 NP, P, M, HN, and L proteins (25), PIV5 V (raised against the C terminus; a kind gift from R. Lamb), phospho-IRF3 (Cell Signaling Technology), GFP (Roche), and ␤-actin (Sigma).…”

Section: Methodsmentioning

confidence: 99%

Deep Sequencing Analysis of Defective Genomes of Parainfluenza Virus 5 and Their Role in Interferon Induction

Killip

Young

Gatherer

et al. 2013

J Virol

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c Preparations of parainfluenza virus 5 (PIV5) that are potent activators of the interferon (IFN) induction cascade were generated by high-multiplicity passage in order to accumulate defective interfering virus genomes (DIs). Nucleocapsid RNA from these virus preparations was extracted and subjected to deep sequencing. Sequencing data were analyzed using methods designed to detect internal deletion and "copyback" DIs in order to identify and characterize the different DIs present and to approximately quantify the ratio of defective to nondefective genomes. Trailer copybacks dominated the DI populations in IFN-inducing preparations of both the PIV5 wild type (wt) and PIV5-V⌬C (a recombinant virus that does not encode a functional V protein). Although the PIV5 V protein is an efficient inhibitor of the IFN induction cascade, we show that nondefective PIV5 wt is unable to prevent activation of the IFN response by coinfecting copyback DIs due to the interfering effects of copyback DIs on nondefective virus protein expression. As a result, copyback DIs are able to very rapidly activate the IFN induction cascade prior to the expression of detectable levels of V protein by coinfecting nondefective virus. The interferon (IFN) response is extremely potent at restricting virus replication and spread prior to activation of the adaptive immune system. IFN-␣ and -␤ are synthesized and secreted from cells in response to virus infection, and this leads to the establishment of an antiviral state in the infected cell and neighboring uninfected cells through the upregulation of hundreds of IFNstimulated genes (ISGs) that together function to make the cell a hostile environment for virus replication. Triggering of the IFN-␤ promoter during infection with paramyxoviruses and other negative-sense viruses occurs through activation of cytosolic pattern recognition receptors (PRRs). The best characterized of these are RIG-I and mda-5, which become activated upon binding of viral pathogen-associated molecular patterns (PAMPs). The viral PAMPs that activate RIG-I and mda-5 are viral RNA molecules; RIG-I is thought to recognize primarily short double-stranded RNAs (dsRNAs) with an uncapped triphosphate moiety, while mda-5 is activated by longer dsRNAs (1-6). Following their activation by PAMP binding, RIG-I and mda-5 elicit a downstream signaling cascade that culminates in the nuclear translocation of the IFN regulatory factor 3 (IRF3) and NF-B transcription factors and subsequent transcription from the IFN-␤ gene. In order to circumvent the powerful IFN response, most viruses have evolved mechanisms to evade it, by encoding viral factors that inhibit IFN induction, the ability of IFN to upregulate ISGs, or the function of certain ISG products (reviewed in reference 7).Parainfluenza virus 5 (PIV5; formerly simian virus 5 [SV5]) is a prototype member of the genus Rubulavirus in the Paramyxoviridae family. The ϳ15-kb negative-sense genomic RNA encodes eight gene products from its seven genes and carries noncoding leader (Le) and trailer (Tr...

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“…Immunofluorescence, immunoprecipitation, SDS͞PAGE, and immunoblot analysis were carried out as described (48,50). Plaque staining for immunological specificity (A͞Udorn͞72) was also performed as described (41).…”

Section: Methodsmentioning

confidence: 99%

Influenza A virus NS1 protein binds p85β and activates phosphatidylinositol-3-kinase signaling

Hale

Jackson

Chen

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

263

331

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Influenza A virus NS1 is a multifunctional protein, and in virusinfected cells NS1 modulates a number of host-cell processes by interacting with cellular factors. Here, we report that NS1 binds directly to p85␤, a regulatory subunit of phosphatidylinositol-3-kinase (PI3K), but not to the related p85␣ subunit. Activation of PI3K in influenza virus-infected cells depended on genome replication, and showed kinetics that correlated with NS1 expression. Additionally, it was found that expression of NS1 alone was sufficient to constitutively activate PI3K, causing the phosphorylation of a downstream mediator of PI3K signal transduction, Akt. Mutational analysis of a potential SH2-binding motif within NS1 indicated that the highly conserved tyrosine at residue 89 is important for both the interaction with p85␤, and the activation of PI3K. A mutant influenza virus (A͞Udorn͞72) expressing NS1 with the Y89F amino acid substitution exhibited a small-plaque phenotype, and grew more slowly in tissue culture than WT virus. These data suggest that activation of PI3K signaling in influenza A virus-infected cells is important for efficient virus replication.Akt phosphorylation ͉ multifunctional NS1 protein ͉ reverse genetics

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Interferon-Induced Alterations in the Pattern of Parainfluenza Virus 5 Transcription and Protein Synthesis and the Induction of Virus Inclusion Bodies

Cited by 30 publications

References 36 publications

Human Bocavirus VP2 Upregulates IFN-β Pathway by Inhibiting Ring Finger Protein 125–Mediated Ubiquitination of Retinoic Acid–Inducible Gene-I

Human Bocavirus VP2 Upregulates IFN-β Pathway by Inhibiting Ring Finger Protein 125–Mediated Ubiquitination of Retinoic Acid–Inducible Gene-I

Deep Sequencing Analysis of Defective Genomes of Parainfluenza Virus 5 and Their Role in Interferon Induction

Influenza A virus NS1 protein binds p85β and activates phosphatidylinositol-3-kinase signaling

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