Deubiquitination in virus infection

Biotechnology Research Institute, National Research Council of Canada, 6100 Avenue Royalmount, Montreal, Quebec, Canada H4P 2R2.
Virology (Impact Factor: 3.32). 07/2007; 362(2):245-56. 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.

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    • "In doing so, DUBs maintain balance of ubiquitination dynamics, playing an editing role analogous to that of the phosphatases in kinase/phosphatase regulatory pathways. Deubiquitination is a highly regulated process that has been implicated in numerous cellular functions, including cell-cycle regulation (Song and Rape, 2008), proteasome-and lysosome-dependent protein degradation (Guterman and Glickman, 2004), gene expression, kinase activation (Grabbe et al., 2011; Skaug et al., 2009), microbial pathogenesis (Lindner, 2007; Rytkö nen and Holden, 2007), and DNA repair (Huang and D'Andrea, 2006; Messick and Greenberg, 2009). Mutations in several DUBs have been linked to diseases ranging from cancer to neurological disorders (Fraile et al., 2012; Sacco et al., 2010; Singhal et al., 2008; Todi and Paulson, 2011). "
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    ABSTRACT: Deubiquitinating enzymes (DUBs) constitute a large family of cysteine proteases that have a broad impact on numerous biological and pathological processes, including the regulation of genomic stability. DUBs are often assembled onto multiprotein complexes to assist in their localization and substrate selection, yet it remains unclear how the enzymatic activity of DUBs is modulated by intracellular signals. Herein, we show that bursts of reactive oxygen species (ROS) reversibly inactivate DUBs through the oxidation of the catalytic cysteine residue. Importantly, USP1, a key regulator of genomic stability, is reversibly inactivated upon oxidative stress. This, in part, explains the rapid nature of PCNA monoubiquitination-dependent DNA damage tolerance in response to oxidative DNA damage in replicating cells. We propose that DUBs of the cysteine protease family act as ROS sensors in human cells and that ROS-mediated DUB inactivation is a critical mechanism for fine-tuning stress-activated signaling pathways.
    Full-text · Article · Dec 2012 · Cell Reports
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    • "Taking into account the importance of ubiquitin-ligase and ubiquitin-proteasome systems for the function of eukaryotic cells, the role of viruses in regulation of these processes has been intensively studied recently. Although the data on this topic are sparse, it has been already discovered that viruses of various families can influence the protein ubiquitination to overcome the cell defense mechanisms, including apoptosis, type I interferon response, and antigen presentation by the class I major histocompatibility complex [45] [47] [48]. "
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    ABSTRACT: In the course of evolution, viruses have developed various molecular mechanisms to evade the defense reactions of the host organism. When understanding the mechanisms used by viruses to overcome manifold defense systems of the animal organism, represented by molecular factors and cells of the immune system, we would not only comprehend better but also discover new patterns of organization and function of these most important reactions directed against infectious agents. Here, study of the orthopoxviruses pathogenic for humans, such as variola (smallpox), monkeypox, cowpox, and vaccinia viruses, may be most important. Analysis of the experimental data, presented in this paper, allows to infer that variola virus and other orthopoxviruses possess an unexampled set of genes whose protein products efficiently modulate the manifold defense mechanisms of the host organisms compared with the viruses from other families.
    Full-text · Article · Jul 2012 · Advances in Virology
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    • "Interference with either arm of this pathway should allow highly targeted pharmacological intervention, provided that compounds with sufficient selectivity can be identified (Refs 3, 4, 5, 6, 7, 8, 9) (Fig. 1). Additional opportunities are provided by the discovery of pathogen-encoded factors that evolved to target the UPS of the host cell, representing attractive targets for treatments against infectious diseases (Refs 10, 11, 12). Therefore, the UPS offers a source of novel pharmacological targets as the basis for the successful development of drugs to treat human diseases. "
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    ABSTRACT: Recent advances in the development and discovery of pharmacological interventions within the ubiquitin-proteasome system (UPS) have uncovered an enormous potential for possible novel treatments of neurodegenerative disease, cancer, immunological disorder and microbial infection. Interference with proteasome activity, although initially considered unlikely to be exploitable clinically, has already proved to be very effective against haematological malignancies, and more specific derivatives that target subsets of proteasomes are emerging. Recent small-molecule screens have revealed inhibitors against ubiquitin-conjugating and -deconjugating enzymes, many of which have been evaluated for their potential use as therapeutics, either as single agents or in synergy with other drugs. Here, we discuss recent advances in the characterisation of novel UPS modulators (in particular, inhibitors of ubiquitin-conjugating and -deconjugating enzymes) and how they pave the way towards new therapeutic approaches for the treatment of proteotoxic disease, cancer and microbial infection.
    Full-text · Article · Nov 2011 · Expert Reviews in Molecular Medicine
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