Ubiquitin-Specific Peptidase 20 Targets TRAF6 and Human T Cell Leukemia Virus Type 1 Tax To Negatively Regulate NF-{kappa}B Signaling

Molecular Virology Section, Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Journal of Virology (Impact Factor: 4.44). 07/2011; 85(13):6212-9. DOI: 10.1128/JVI.00079-11
Source: PubMed


NF-κB plays a key role in innate and acquired immunity. Its activity is regulated through intricate signaling networks. Persistent
or excessive activation of NF-κB induces diseases, such as autoimmune disorders and malignant neoplasms. Infection by human
T cell leukemia virus type 1 (HTLV-1) causes a fatal hematopoietic malignancy termed adult T cell leukemia (ATL). The HTLV-1
viral oncoprotein Tax functions pivotally in leukemogenesis through its potent activation of NF-κB. Recent findings suggest
that protein ubiquitination is crucial for proper regulation of NF-κB signaling and for Tax activity. Here, we report that
ubiquitin-specific peptidase USP20 deubiquitinates TRAF6 and Tax and suppresses interleukin 1β (IL-1β)- and Tax-induced NF-κB
activation. Our results point to USP20 as a key negative regulator of Tax-induced NF-κB signaling.

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    • "By using a siRNA screen, we found that knockdowns of several USPs potently potentiated SEV-induced activation of the ISRE promoter, some of which had been reported as being associated with the NF-κB signaling pathway. For example, USP11 negatively regulates TNFα-induced NF-κB activation associated with IκBα and attenuates IκBα degradation [34]; USP20 deubiquitinates TRAF6 and suppresses interleukin 1β (IL-1β)- and Tax-induced NF-κB activation [40]; Katrin et al. showed that USP15 regulates IκBα/NF-κB by deubiquitinylation IκBα[44]; and USP31 inhibits TNFα, CD40, TRAF2, TRAF6 and IKKβ-mediated NF-κB activation [45]. "
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    ABSTRACT: Ubiquitination and deubiquitination have emerged as critical regulatory processes in the virus-triggered type I interferon (IFN) induction pathway. In this study, we carried out a targeted siRNA screen of 54 ubiquitin-specific proteases (USPs) and identified USP25 as a negative regulator of the virus-triggered type I IFN signaling pathway. Overexpression of USP25 inhibited virus-induced activation of IFN-β, interferon regulation factor 3 (IRF3) and nuclear factor-kappa B (NF-κB), as well as the phosphorylation of IRF3 and NF-κB subunit p65. Furthermore, Knockdown of USP25 potentiated virus-induced induction of the IFN-β. In addition, detailed analysis demonstrated that USP25 cleaved lysine 48- and lysine 63-linked polyubiquitin chains in vitro and in vivo, and its deubiquitinating enzyme (DUB) activity, were dependent on a cysteine residue (Cys178) and a histidine residue (His607). USP25 mutants lacking DUB activity lost the ability to block virus-induced type I IFN to some degree. Mechanistically, USP25 deubiquitinated retinoic acid-inducible gene I (RIG-I), tumornecrosis factor (TNF) receptor-associated factor 2 (TRAF2), and TRAF6 to inhibit RIG-I-like receptor-mediated IFN signaling. Our findings suggest that USP25 is a novel DUB negatively regulating virus-induced type I IFN production.
    PLoS ONE 11/2013; 8(11):e80976. DOI:10.1371/journal.pone.0080976 · 3.23 Impact Factor
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    • "Other cellular proteins are important for Tax-mediated NF-κB activation. Tax-1 interacts with NRP/optineurin and TAX1BP1 (Journo et al., 2009; Shembade et al., 2011), and with the ubiquitin-specific peptidase USP20 (Yasunaga et al., 2011). A recent study demonstrated that Tax-1 promotes Bcl-3 expression and nuclear translocation of RelA/p65 (Gao et al., 2013). "
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    ABSTRACT: Human T cell leukemia viruses (HTLVs) are complex human retroviruses of the Deltaretrovirus genus. Four types have been identified thus far, with HTLV-1 and HTLV-2 much more prevalent than HTLV-3 or HTLV-4. HTLV-1 and HTLV-2 possess strictly related genomic structures, but differ significantly in pathogenicity, as HTLV-1 is the causative agent of adult T cell leukemia and of HTLV-associated myelopathy/tropical spastic paraparesis, whereas HTLV-2 is not associated with neoplasia. HTLVs code for a protein named Tax that is responsible for enhancing viral expression and drives cell transformation. Much effort has been invested to dissect the impact of Tax on signal transduction pathways and to identify functional differences between the HTLV Tax proteins that may explain the distinct oncogenic potential of HTLV-1 and HTLV-2. This review summarizes our current knowledge of Tax-1 and Tax-2 with emphasis on their structure, role in activation of the NF-κB (nuclear factor kappa-B) pathway, and interactions with host factors.
    Frontiers in Microbiology 09/2013; 4:271. DOI:10.3389/fmicb.2013.00271 · 3.99 Impact Factor
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    • "Another deubiquitinase, Ubiquitin-specific peptidase 20 (USP20), was also shown to reduce Tax ubiquitination and consequently inhibit Tax-mediated upregulation of the NF-κB pathway. Similar to CYLD, though, USP20 is found to be down regulated in HTLV-1 transformed cells although the mechanism of the USP20 suppression has not been elucidated (Yasunaga et al., 2011). "
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    ABSTRACT: Human T-cell lymphotropic virus type 1 (HTLV-1) has been identified as the causative agent of adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The virus infects between 15 and 20 million people worldwide of which approximately 2-5% develop ATL. The past 35 years of research have yielded significant insight into the pathogenesis of HTLV-1, including the molecular characterization of Tax, the viral transactivator, and oncoprotein. In spite of these efforts, the mechanisms of oncogenesis of this pleiotropic protein remain to be fully elucidated. In this review, we illustrate the multiple oncogenic roles of Tax by summarizing a recent body of literature that refines our understanding of cellular transformation. A focused range of topics are discussed in this review including Tax-mediated regulation of the viral promoter and other cellular pathways, particularly the connection of the NF-κB pathway to both post-translational modifications (PTMs) of Tax and subcellular localization. Specifically, recent research on polyubiquitination of Tax as it relates to the activation of the IkappaB kinase (IKK) complex is highlighted. Regulation of the cell cycle and DNA damage responses due to Tax are also discussed, including Tax interaction with minichromosome maintenance proteins and the role of Tax in chromatin remodeling. The recent identification of HTLV-3 has amplified the importance of the characterization of emerging viral pathogens. The challenge of the molecular determination of pathogenicity and malignant disease of this virus lies in the comparison of the viral transactivators of HTLV-1, -2, and -3 in terms of transformation and immortalization. Consequently, differences between the three proteins are currently being studied to determine what factors are required for the differences in tumorogenesis.
    Frontiers in Microbiology 11/2012; 3:406. DOI:10.3389/fmicb.2012.00406 · 3.99 Impact Factor
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