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Roger D Everett - One of the best experts on this subject based on the ideXlab platform.
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the herpes simplex virus icp0 RING Finger Domain inhibits irf3 and irf7 mediated activation of interferon stimulated genes
Journal of Virology, 2004Co-Authors: Rongtuan Lin, Roger D Everett, Ryan S Noyce, Susan E Collins, Karen L MossmanAbstract:Virus infection induces a rapid cellular response in cells characterized by the induction of interferon. While interferon itself does not induce an antiviral response, it activates a number of interferon-stimulated genes that collectively function to inhibit virus replication and spread. Previously, we and others reported that herpes simplex virus type 1 (HSV-1) induces an interferon -independent antiviral response in the absence of virus replication. Here, we report that the HSV-1 proteins ICP0 and vhs function in concert to disable the host antiviral response. In particular, we show that ICP0 blocks interferon regulatory factor IRF3- and IRF7-mediated activation of interferon-stimulated genes and that the RING Finger Domain of ICP0 is essential for this activity. Furthermore, we demonstrate that HSV-1 modifies the IRF3 pathway in a manner different from that of the small RNA viruses most commonly studied.
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herpes simplex virus type 1 immediate early protein icp0 and its isolated RING Finger Domain act as ubiquitin e3 ligases in vitro
Journal of Virology, 2002Co-Authors: Chris Boutell, Seth Sadis, Roger D EverettAbstract:Proteasome-dependent degradation of ubiquitinated proteins plays a key role in many important cellular processes. Ubiquitination requires the E1 ubiquitin activating enzyme, an E2 ubiquitin conjugating enzyme, and frequently a substrate-specific ubiquitin protein ligase (E3). One class of E3 ubiquitin ligases has been shown to contain a common zinc-binding RING Finger motif. We have previously shown that herpes simplex virus type 1 ICP0, itself a RING Finger protein, induces the proteasome-dependent degradation of several cellular proteins and induces the accumulation of colocalizing conjugated ubiquitin in vivo. We now report that both full-length ICP0 and its isolated RING Finger Domain induce the accumulation of polyubiquitin chains in vitro in the presence of E1 and the E2 enzymes UbcH5a and UbcH6. Mutations within the RING Finger region that abolish the in vitro ubiquitination activity also cause severe reductions in ICP0 activity in other assays. We conclude that ICP0 has the potential to act as an E3 ubiquitin ligase duRING viral infection and to target specific cellular proteins for destruction by the 26S proteasome.
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Alphaherpesvirus Proteins Related to Herpes Simplex Virus Type 1 ICP0 Affect Cellular Structures and Proteins
Journal of virology, 2000Co-Authors: Jane Parkinson, Roger D EverettAbstract:The herpes simplex virus type 1 (HSV-1) immediate-early protein ICP0 interacts with several cellular proteins and induces the proteasome-dependent degradation of others duRING infection. In this study we show that ICP0 is required for the proteasome-dependent degradation of the ND10 protein Sp100 and, as with the other target proteins, the ICP0 RING Finger Domain is essential. Further, comparison of the kinetics and ICP0 Domain requirements for the degradation of PMI and Sp100 suggests that a common mechanism is involved. Homologues of ICP0 are encoded by other members of the alphaherpesvirus family. These proteins show strong sequence homology to ICP0 within the RING Finger Domain but limited similarity elsewhere. Using transfection assays, we have shown that all the ICP0 homologues that we tested have significant effects on the immunofluorescence staining character of at least one of the proteins destabilized by ICP0, and by using a recombinant virus, we found that the equine herpesvirus ICP0 homologue induced the proteasome-dependent degradation of endogenous CENP-C and modified forms of PML and Sp100. However, in contrast to ICP0, the homologue proteins had no effect on the distribution of the ubiquitin-specific protease USP7 within the cell, consistent with their lack of a USP7 binding Domain. We also found that ICP0 by itself could induce the abrogation of SUMO-1 conjugation and then the proteasome-dependent degradation of unmodified exogenous PML in transfected cells, thus demonstrating that other HSV-1 proteins are not required. Surprisingly, the ICP0 homologues were unable to cause these effects. Overall, these data suggest that the members of the ICP0 family of proteins may act via a similar mechanism or pathway involving their RING Finger Domain but that their intrinsic activities and effects on endogenous and exogenous proteins differ in detail.
Isabelle Callebaut - One of the best experts on this subject based on the ideXlab platform.
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Rare RNF213 variants in the C-terminal region encompassing the RING-Finger Domain are associated with moyamoya angiopathy in Caucasians
European Journal of Human Genetics, 2017Co-Authors: Stéphanie Guey, Markus Kraemer, Dominique Hervé, Thomas Ludwig, Manoelle Kossorotoff, Françoise Bergametti, Jan Claudius Schwitalla, Simone Choi, Lucile Broseus, Isabelle CallebautAbstract:Moyamoya angiopathy (MMA) is a cerebral angiopathy affecting the terminal part of internal carotid arteries. Its prevalence is 10 times higher in Japan and Korea than in Europe. In East Asian countries, moyamoya is strongly associated to the R4810K variant in the RNF213 gene that encodes for a protein containing a RING-Finger and two AAA+ Domains. This variant has never been detected in Caucasian MMA patients, but several rare RNF213 variants have been reported in Caucasian cases. Using a collapsing test based on exome data from 68 European MMA probands and 573 ethnically matched controls, we showed a significant association between rare missense RNF213 variants and MMA in European patients (odds ratio (OR)=2.24, 95% confidence interval (CI)=(1.19-4.11), P=0.01). Variants specific to cases had higher pathogenicity predictive scores (median of 24.2 in cases versus 9.4 in controls, P=0.029) and preferentially clustered in a C-terminal hotspot encompassing the RING-Finger Domain of RNF213 (P\textless10-3). This association was even stronger when restricting the analysis to childhood-onset and familial cases (OR=4.54, 95% CI=(1.80-11.34), P=1.1 × 10-3). All clinically affected relatives who were genotyped were carriers. However, the need for additional factors to develop MMA is strongly suggested by the fact that only 25% of mutation carrier relatives were clinically affected.
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Rare RNF213 variants in the C-terminal region encompassing the RING-Finger Domain are associated with moyamoya angiopathy in Caucasians.
European journal of human genetics : EJHG, 2017Co-Authors: Stéphanie Guey, Markus Kraemer, Dominique Hervé, Thomas Ludwig, Manoelle Kossorotoff, Françoise Bergametti, Jan Claudius Schwitalla, Simone Choi, Lucile Broseus, Isabelle CallebautAbstract:Moyamoya angiopathy (MMA) is a cerebral angiopathy affecting the terminal part of internal carotid arteries. Its prevalence is 10 times higher in Japan and Korea than in Europe. In East Asian countries, moyamoya is strongly associated to the R4810K variant in the RNF213 gene that encodes for a protein containing a RING-Finger and two AAA+ Domains. This variant has never been detected in Caucasian MMA patients, but several rare RNF213 variants have been reported in Caucasian cases. Using a collapsing test based on exome data from 68 European MMA probands and 573 ethnically matched controls, we showed a significant association between rare missense RNF213 variants and MMA in European patients (odds ratio (OR)=2.24, 95% confidence interval (CI)=(1.19-4.11), P=0.01). Variants specific to cases had higher pathogenicity predictive scores (median of 24.2 in cases versus 9.4 in controls, P=0.029) and preferentially clustered in a C-terminal hotspot encompassing the RING-Finger Domain of RNF213 (P
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rare rnf213 variants in the c terminal region encompassing the RING Finger Domain are associated with moyamoya angiopathy in caucasians
European Journal of Human Genetics, 2017Co-Authors: Stéphanie Guey, Markus Kraemer, Dominique Hervé, Thomas Ludwig, Manoelle Kossorotoff, Françoise Bergametti, Jan Claudius Schwitalla, Simone Choi, Lucile Broseus, Isabelle CallebautAbstract:Moyamoya angiopathy (MMA) is a cerebral angiopathy affecting the terminal part of internal carotid arteries. Its prevalence is 10 times higher in Japan and Korea than in Europe. In East Asian countries, moyamoya is strongly associated to the R4810K variant in the RNF213 gene that encodes for a protein containing a RING-Finger and two AAA+ Domains. This variant has never been detected in Caucasian MMA patients, but several rare RNF213 variants have been reported in Caucasian cases. Using a collapsing test based on exome data from 68 European MMA probands and 573 ethnically matched controls, we showed a significant association between rare missense RNF213 variants and MMA in European patients (odds ratio (OR)=2.24, 95% confidence interval (CI)=(1.19-4.11), P=0.01). Variants specific to cases had higher pathogenicity predictive scores (median of 24.2 in cases versus 9.4 in controls, P=0.029) and preferentially clustered in a C-terminal hotspot encompassing the RING-Finger Domain of RNF213 (P<10-3). This association was even stronger when restricting the analysis to childhood-onset and familial cases (OR=4.54, 95% CI=(1.80-11.34), P=1.1 × 10-3). All clinically affected relatives who were genotyped were carriers. However, the need for additional factors to develop MMA is strongly suggested by the fact that only 25% of mutation carrier relatives were clinically affected.
Jeffrey I. Cohen - One of the best experts on this subject based on the ideXlab platform.
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Varicella-Zoster Virus ORF61 Deletion Mutants Replicate in Cell Culture, but a Mutant with Stop Codons in ORF61 Reverts to Wild-Type Virus
Virology, 1998Co-Authors: Jeffrey I. Cohen, Hanh T. NguyenAbstract:Abstract Varicella-zoster virus (VZV) ORF61 encodes a phosphoprotein that transactivates VZV promoters. Transfection of cells with cosmid DNAs, including a cosmid with a large deletion in ORF61, resulted in a VZV ORF61 deletion mutant that was impaired for growth in vitro and could be partially complemented by growth in neuroblastoma or osteosarcoma cell lines. Cells infected with the VZV ORF61 deletion mutant expressed normal levels of an immediate-early VZV protein, but had reduced levels of a late protein and showed abnormal syncytia. Carboxy terminal truncation mutants of VZV ORF61 protein have a transrepressing phenotype and inhibit the infectivity of cotransfected wild-type viral DNA. Transfection of cells with cosmid DNAs, including a cosmid with stop codons that should result in an ORF61 truncation mutant expressing a transrepressing protein that retains the RING Finger Domain, resulted in a viral genome which reverted back to the wild-type sequence. BAL-31 exonuclease was used to produce deletions at the site of the stop codons in ORF61 of the cosmid, resulting in loss of the RING Finger Domain. Transfection of tissue culture cells with the ORF61 BAL-31 deletion mutants and other cosmid DNAs yielded viable viruses. Thus, while deletion mutants lacking the RING Finger Domain of ORF61 replicate in cell culture, a mutant with stop codons that retains this Domain could not be propagated and reverted to wild-type virus.
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The RING Finger Domain of the varicella-zoster virus open reading frame 61 protein is required for its transregulatory functions.
Virology, 1994Co-Authors: Hiroyuki Moriuchi, Masako Moriuchi, Jeffrey I. CohenAbstract:Abstract Varicella-zoster virus (VZV) open reading frame 61 (ORF61) protein transactivates expression of VZV promoters. VZV ORF61 is functionally homologous to herpes simplex virus type 1 (HSV-1)-infected cell protein 0 (ICPO); however, amino acid sequence homology of these two proteins is limited to the RING Finger Domains, a recently identified sequence motif composed of cysteine and histidine residues, located in their amino-terminal regions. A carboxy-terminal truncation mutant of ICPO (which retains the RING Finger Domain) was previously shown to act as a potent transrepressor and as a dominant-negative mutant in the presence of full-length ICPO. We have shown that the corresponding region of ORF61 has similar properties. Amino-terminal truncation mutants of VZV ORF61 and HSV-1 ICPO, which lack the RING Finger Domain, cannot transactivate VZV promoters; however, fusion of the amino portion of one protein to the carboxy portion of the other restored the transactivating activity of the full-length proteins. To further study the role of the ORF61 RING Finger Domain, cysteine or histidine residues of this Domain were individually replaced with serine or aspargine, respectively. Each of these amino acid substitution mutants in the RING Finger abolished the transactivating activity of the full-length ORF61 protein. Each of the substitutions also reduced the transrepressing and dominant-negative properties of a carboxy-terminal truncation mutant of ORF61. These results indicate that the RING Finger Domain is required for the transregulatory functions of ORF61.
S Watanabe - One of the best experts on this subject based on the ideXlab platform.
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Mapping of transregulatory Domains of pseudorabies virus early protein 0 and identification of its dominant-negative mutant
Archives of Virology, 1996Co-Authors: S Watanabe, Y. Shimizu, H KidaAbstract:Pseudorabies virus (PRV) early protein 0 (EP0) is a transactivator containing the RING Finger Domain. Analysis of transactivating activity of truncated forms of the EP0 molecule consisting of 410 amino acids revealed that amino-terminal region containing the RING Finger Domain, amino acids 1 to 84, and the region between amino acids 114 to 242 containing acidic amino acid sequences were required for the transactivation. On the other hand, the mutant consisting of amino acids 1 to 113 exhibited a dominant-negative property.
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Pseudorabies virus early protein 0 transactivates the viral gene promoters.
Journal of General Virology, 1995Co-Authors: S Watanabe, Yukio Shimizu, E Ono, Hiroshi KidaAbstract:Pseudorabies virus (PRV) early protein 0 (EP0) contains the RING Finger Domain with homology to the immediate-early (IE) protein ICP0 of herpes simplex virus type 1 (HSV-1). EP0 was detected by indirect immunofluorescence in the nuclei of the cells transfected with EP0 expression plasmid as is the case in cells infected with PRV. In transient expression assays, EP0 trans-activated the PRV IE, thymidine kinase (TK) and glycoprotein X (gX) promoters, indicating that EP0, like ICP0 of HSV-1, is a transactivating protein.
Hiroshi Kida - One of the best experts on this subject based on the ideXlab platform.
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Pseudorabies virus early protein 0 transactivates the viral gene promoters.
Journal of General Virology, 1995Co-Authors: S Watanabe, Yukio Shimizu, E Ono, Hiroshi KidaAbstract:Pseudorabies virus (PRV) early protein 0 (EP0) contains the RING Finger Domain with homology to the immediate-early (IE) protein ICP0 of herpes simplex virus type 1 (HSV-1). EP0 was detected by indirect immunofluorescence in the nuclei of the cells transfected with EP0 expression plasmid as is the case in cells infected with PRV. In transient expression assays, EP0 trans-activated the PRV IE, thymidine kinase (TK) and glycoprotein X (gX) promoters, indicating that EP0, like ICP0 of HSV-1, is a transactivating protein.
