Deubiquitination in virus infection

ArticleinVirology 362(2):245-56 · July 2007with25 Reads
DOI: 10.1016/j.virol.2006.12.035 · Source: PubMed
Post-translational modification of proteins and peptides by ubiquitin, a highly evolutionarily conserved 76 residue protein, and ubiquitin-like modifiers has emerged as a major regulatory mechanism in various cellular activities. Eukaryotic viruses are known to modulate protein ubiquitination to their advantage in various ways. At the same time, the evidence for the importance of deubiquitination as a viral target also is growing. This review centers on known viral interactions with protein deubiquitination, on viral enzymes for which deubiquitinating activities were recently demonstrated, and on the roles of viral ubiquitin-like sequences.
    • "Whether this domain is a degenerate partially functional or non-functional protease domain, or an entirely different domain or protein, remains to be clarified. One other study has reported deubiquitination activity, a key target for viral infection [49], associated with a recombinant protein comprising the methyltransferase, Y-domain and protease domain (amino acids 22-592) of HEV ORF1 [50] . A later study showed that a recombinant HEV protease domain, when expressed in HEK293T cells, resulted in reduced IFNβ mRNA production and deubiquitination of RIG-I and TBK-1 [51]. "
    [Show abstract] [Hide abstract] ABSTRACT: Background Hepatitis E virus (HEV) is an enteric, single-stranded, positive sense RNA virus and a significant etiological agent of hepatitis, causing sporadic infections and outbreaks globally. Tracing the evolutionary ancestry of HEV has proved difficult since its identification in 1992, it has been reclassified several times, and confusion remains surrounding its origins and ancestry. ResultsTo reveal close protein relatives of the Hepeviridae family, similarity searching of the GenBank database was carried out using a complete Orthohepevirus A, HEV genotype I (GI) ORF1 protein sequence and individual proteins. The closest non-Hepeviridae homologues to the HEV ORF1 encoded polyprotein were found to be those from the lepidopteran-infecting Alphatetraviridae family members. A consistent relationship to this was found using a phylogenetic approach; the Hepeviridae RdRp clustered with those of the Alphatetraviridae and Benyviridae families. This puts the Hepeviridae ORF1 region within the “Alpha-like” super-group of viruses. In marked contrast, the HEV GI capsid was found to be most closely related to the chicken astrovirus capsid, with phylogenetic trees clustering the Hepeviridae capsid together with those from the Astroviridae family, and surprisingly within the “Picorna-like” supergroup. These results indicate an ancient recombination event has occurred at the junction of the non-structural and structure encoding regions, which led to the emergence of the entire Hepeviridae family.The Astroviridae capsid is also closely related to the Tymoviridae family of monopartite, T = 3 icosahedral plant viruses, whilst its non-structural region is related to viruses of the Potyviridae; a large family of plant-infecting viruses with a flexible filamentous rod-shaped virion. Thus, we identified a separate inter-viral family recombination event, again at the non-structural/structural junction, which likely led to the creation of the Astroviridae. Conclusions In summary, we have shown that new viral families have been created though recombination at the junction of the genome that encodes non-structural and structural proteins, and such recombination events are implicated in the genesis of important human pathogens; HEV, astrovirus and rubella virus.
    Full-text · Article · Oct 2016
    • "On the other hand, viruses may also benefit from inhibiting or reversing ubiquitination . For example, baculovirus-encoded Ub homologs can inhibit Ub chain elongation (Haas et al., 1996), and several viruses encode potent deubiquitinating enzymes (Lindner, 2007). Inhibiting or reversing Ub reactions might block the activation of the IMD pathway and/or may prevent the direct targeting of viral proteins for destruction by the host UPS. "
    [Show abstract] [Hide abstract] ABSTRACT: eLife digest Viruses can infect species as diverse as bacteria, plants and animals, and once they have infected an organism they hijack its cells to rapidly replicate their own genetic material, which is made of DNA or RNA. Many animals, including insects, have been used as model organisms to investigate viral infections. These studies have, for example, provided insights into how viruses replicate and how they suppress their host's immune system. One insect species that has been used in many virus-host studies is the gypsy moth. This species of moth was accidently introduced into North America from Europe in the late 1800s, and its caterpillars have become a major pest because they destroy hardwood trees and forests. Gypsy moth outbreaks are still a serious problem, but their numbers can be kept in check by using biological control strategies, such as DNA viruses. However, the response of gypsy moths to infection by RNA viruses has not been studied extensively. Gammon et al. now show that, after being infected with one of two different RNA viruses, gypsy moth cells can slow down and eventually halt the replication of the RNA viruses. However, if the gypsy moth cells are also infected with a DNA virus, they lose their ability to restrict the replication of the RNA virus. Gammon et al. discovered that the moth’s immunity to RNA virus infection is disarmed by a protein called A51R from the DNA virus. This protein increases the stability of the proteins in the RNA virus, most likely by stopping the moth from breaking them down. The results of Gammon et al. suggest that it might be possible to use a combination of RNA viruses and the A51R protein to keep the number of gypsy moths in check. DOI:
    Full-text · Article · Jun 2014
    • "Viruses constantly take advantage of this pathway by modifying ubiquitination of cellular proteins, or their own proteins, to allow for increased replication efficacy [45,46]. For example, DUBs such as USP9x and USP7 have been shown to aid in stabilization of proteins needed for EBV and HSV-1 infection [45,48,49], suggesting that their inhibition could provide ways to control or inhibit viral replication. Thus, targeting these DUBs with WP1130 or its derivatives could provide a way to counter a viral pathogen's attack on host cells. "
    [Show abstract] [Hide abstract] ABSTRACT: Most antiviral treatment options target the invading pathogen and unavoidably encounter loss of efficacy as the pathogen mutates to overcome replication restrictions. A good strategy for circumventing drug resistance, or for pathogens without treatment options, is to target host cell proteins that are utilized by viruses during infection. The small molecule WP1130 is a selective deubiquitinase inhibitor shown previously to successfully reduce replication of noroviruses and some other RNA viruses. In this study, we screened a library of 31 small molecule derivatives of WP1130 to identify compounds that retained the broad-spectrum antiviral activity of the parent compound in vitro but exhibited improved drug-like properties, particularly increased aqueous solubility. Seventeen compounds significantly reduced murine norovirus infection in murine macrophage RAW 264.7 cells, with four causing decreases in viral titers that were similar or slightly better than WP1130 (1.9 to 2.6 log scale). Antiviral activity was observed following pre-treatment and up to 1 hour postinfection in RAW 264.7 cells as well as in primary bone marrow-derived macrophages. Treatment of the human norovirus replicon system cell line with the same four compounds also decreased levels of Norwalk virus RNA. No significant cytotoxicity was observed at the working concentration of 5 µM for all compounds tested. In addition, the WP1130 derivatives maintained their broad-spectrum antiviral activity against other RNA viruses, Sindbis virus, LaCrosse virus, encephalomyocarditis virus, and Tulane virus. Thus, altering structural characteristics of WP1130 can maintain effective broad-spectrum antiviral activity while increasing aqueous solubility.
    Full-text · Article · Apr 2014
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