C Terminal CYS-RICH Region of Mumps Virus Structural V Protein Correlates with Block of Interferon α and γ Signal Transduction Pathway through Decrease of STAT 1-α

Kubota, Takeshi; Yokosawa, Noriko; Yokota, Shinichi; Fujii, Nobuhiro

doi:10.1006/bbrc.2001.4764

Cited by 133 publications

(118 citation statements)

References 10 publications

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“…For some paramyxoviruses, the CTD has been demonstrated to be required for V protein function in IFN antagonism (6,9,16). Furthermore, for several paramyxoviruses, expression of the isolated CTD alone has been reported to evade IFN responses (10,16,21). However, expression of the CTD alone is not sufficient for IFN evasion by all species tested (e.g., compare results for Newcastle disease virus and Nipah virus V in reference 21) and notably fails to copurify proteins important for Rubulavirus V protein-dependent ubiquitin ligase complexes (28).…”

Section: Discussionmentioning

confidence: 99%

Identification of the Nuclear Export Signal and STAT-Binding Domains of the Nipah Virus V Protein Reveals Mechanisms Underlying Interferon Evasion

Rodriguez

Cruz

Horvath

2004

J Virol

124

123

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The V proteins of Nipah virus and Hendra virus have been demonstrated to bind to cellular STAT1 and STAT2 proteins to form high-molecular-weight complexes that inhibit interferon (IFN)-induced antiviral transcription by preventing STAT nuclear accumulation. Analysis of the Nipah virus V protein has revealed a region between amino acids 174 and 192 that functions as a CRM1-dependent nuclear export signal (NES).This peptide is sufficient to complement an export-defective human immunodeficiency virus Rev protein, and deletion and substitution mutagenesis revealed that this peptide is necessary for both V protein shuttling and cytoplasmic retention of STAT1 and STAT2 proteins. However, the NES is not required for V-dependent IFN signaling inhibition. IFN signaling is blocked primarily by interaction between Nipah virus V residues 100 to 160 and STAT1 residues 509 to 712. Interaction with STAT2 requires a larger Nipah virus V segment between amino acids 100 and 300, but deletion of residues 230 to 237 greatly reduced STAT2 coprecipitation. Further, V protein interactions with cellular STAT1 is a prerequisite for STAT2 binding, and sequential immunoprecipitations demonstrate that V, STAT1, and STAT2 can form a tripartite complex. These findings characterize essential regions for Henipavirus V proteins that represent potential targets for therapeutic intervention.The biological effects of alpha and beta interferon (IFN-␣ and -␤) are mediated by a transcription factor complex, ISGF3, that is comprised of the signal transducer and activator of transcription (STAT) proteins, STAT1 and STAT2, in association with a DNA-binding subunit, an IFN regulatory factor, IRF9 (1, 12). IFN-induced, ISGF3-mediated transcription results in a cellular antiviral state that provides protection against a broad range of virus types. In response to this negative selection, most viruses have evolved adaptations that allow them to evade IFN-induced innate antiviral responses (13,26).In the case of the paramyxovirus family of negative-strand RNA viruses, IFN signaling to ISGF3 is disrupted by direct targeting of STAT proteins (4). Current evidence from the study of several family members indicates that the common outcome of STAT targeting and IFN evasion is achieved by individual paramyxovirus species through a diverse range of molecular mechanisms. For example, the Rubulaviruses, simian virus 5 (SV5), human parainfluenza virus 2, and mumps virus all encode STAT-directed E3 ubiquitin ligase activities that function in combination with cellular proteins to target STAT1, STAT2, or STAT3 for proteasomal degradation (5,18,19,28,29). Distinctly, measles virus, a prototype Morbillivirus, does not induce STAT ubiquitylation and degradation but instead prevents IFN-induced ISGF3 assembly and STAT protein nuclear translocation (17, 27). These IFN evasion mechanisms rely on protein-protein interactions between STATs and the paramyxovirus-encoded V protein. The paramyxovirus V protein is characterized by a highly conserved cysteine-rich C-terminal domain (...

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Section: Discussionmentioning

confidence: 99%

Identification of the Nuclear Export Signal and STAT-Binding Domains of the Nipah Virus V Protein Reveals Mechanisms Underlying Interferon Evasion

Rodriguez

Cruz

Horvath

2004

J Virol

124

123

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“…Cell Viability-Cell viability was determined by a gentian violet dye binding assay as previously described (20). The binding dye was solubilized by 2-methoxyethanol, and absorbance at 595 nm was measured.…”

Section: Methodsmentioning

confidence: 99%

“…Human parainfluenza virus type 2 reduces STAT-2 protein levels (22,23). Accelerated degradation of STAT-1 by mumps virus is necessary and sufficient for the expression of viral accessory protein V (20,21,24). These STAT proteins act as transcription factors for IFN-inducible genes, so that the decrease in the proteins leads not only to a reduction of the antiviral state but also to other IFN-induced cellular responses.…”

mentioning

confidence: 99%

Suppression of Thermotolerance in Mumps Virus-infected Cells Is Caused by Lack of HSP27 Induction Contributed by STAT-1

Yokota

Yokosawa

Kubota

et al. 2003

Journal of Biological Chemistry

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Viral infection modulates the regulation of apoptosis in host cells. Here, we report a novel mechanism by which human cells infected with mumps virus become susceptible to apoptosis caused by extracellular stresses. Mumps virus stimulates proteasome-dependent degradation of STAT-1 by action of viral accessory protein V, resulting in a severe decrease in STAT-1 protein in infected cells. We exposed mumps virus-infected and uninfected cells to heat and chemical stress. The infected cells failed to acquire resistance to apoptotic stimuli (thermotolerance) after exposure to these mild stresses. The induction of HSP27 by stress exposure was dramatically suppressed in the infected cells, but HSP70 induction was not affected. STAT-1 was required for transcriptional activation of the HSP27 gene, but not for the HSP70 gene, and cDNA transfection of STAT-1 in mumps virus-infected cells restored thermotolerance. Phosphorylated heat shock factor-1 (HSF-1) and STAT-1 phosphorylated on neither tyrosine nor serine residues were co-transported to the nucleus in response to stress. Furthermore, overexpression of unphosphorylatable mutants of STAT-1 also restored thermotolerance in mumps virus-infected cells. These lines of evidence indicate that the induction of HSP27 by stress requires STAT-1 in addition to the activated HSF-1. Furthermore, STAT-1 required for the induction of HSP27 worked independent to its phosphorylation. Thus, HSP27-dependent thermotolerance is suppressed by mumps virus infection through the destruction of STAT-1. The lack of thermotolerance should allow the infected cells to be eliminated by apoptosis and might be a host defense against viral infection.

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“…Almost all rubulavirus V proteins target STAT1 or STAT2 for degradation by the host-cell proteosomal pathways [84][85][86][87] through assembly of a V-degradation complex (VDC) containing V protein, STAT1, STAT2, and components of an E3 ubiquitin ligase complex, specifically the UV damage-specific DNA binding protein 1 (DDB1), and Cul4A [88][89][90][91][92] , which likely mediate the STAT1/2 polyubiquitination [93] . In vitro studies/crystallographic analysis of the PIV5 V-DBB1 complex have indicated that both the N-terminal and unique C-terminal regions of PIV5 V are required for VDC assembly and STAT1 degradation [33,88,93,94] .…”

Section: Targeting Of Stats By Rubulaviruses: Degradation and Mis-locmentioning

confidence: 99%

Paramyxovirus evasion of innate immunity: Diverse strategies for common targets

Audsley

Moseley²

2013

WJV

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C Terminal CYS-RICH Region of Mumps Virus Structural V Protein Correlates with Block of Interferon α and γ Signal Transduction Pathway through Decrease of STAT 1-α

Cited by 133 publications

References 10 publications

Identification of the Nuclear Export Signal and STAT-Binding Domains of the Nipah Virus V Protein Reveals Mechanisms Underlying Interferon Evasion

Identification of the Nuclear Export Signal and STAT-Binding Domains of the Nipah Virus V Protein Reveals Mechanisms Underlying Interferon Evasion

Suppression of Thermotolerance in Mumps Virus-infected Cells Is Caused by Lack of HSP27 Induction Contributed by STAT-1

Paramyxovirus evasion of innate immunity: Diverse strategies for common targets

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