Inhibition of proteasomal degradation by the Gly-Ala repeat of Epstein–Barr virus is influenced by the length of the repeat and the strength of the degradation signal

Dantuma, Nico P.; Heessen, Stijn; Lindsten, Kristina; Jellne, Marianne; Masucci, Maria G.

doi:10.1073/pnas.140217397

Cited by 77 publications

(66 citation statements)

References 25 publications

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“…Using an in vitro processing assay, it was shown that the GAr is a specific inhibitor of ubiquitin-dependent proteolysis and acts as a transferable element that, when expressed in the context of other viral or cellular proteasome substrates, abrogates or severely inhibits their degradation (Levitskaya et al, 1997). Several features of this stabilization signal were revealed using a set of GAr chimeras involving IkB (Sharipo et al, 1998), p53 (Heessen et al, 2002) and green fluorescent protein (GFP)-based proteasome substrates in mammalian (Dantuma et al, 2000a) and budding yeast (Heessen et al, in press). It was found that the activity of the GAr is independent of its location in the target protein (Levitskaya et al, 1997;Sharipo et al, 1998;Dantuma et al, 2000a;Heessen et al, 2002) and is not restricted by the type of ubiquitin ligase involved in substrate modification (Sharipo et al, 1998;Dantuma et al, 2000a;Heessen et al, 2002).…”

Section: The Rescue Program: Lmp-2a and The Capture Of Cellular Ubiqumentioning

confidence: 99%

“…Several features of this stabilization signal were revealed using a set of GAr chimeras involving IkB (Sharipo et al, 1998), p53 (Heessen et al, 2002) and green fluorescent protein (GFP)-based proteasome substrates in mammalian (Dantuma et al, 2000a) and budding yeast (Heessen et al, in press). It was found that the activity of the GAr is independent of its location in the target protein (Levitskaya et al, 1997;Sharipo et al, 1998;Dantuma et al, 2000a;Heessen et al, 2002) and is not restricted by the type of ubiquitin ligase involved in substrate modification (Sharipo et al, 1998;Dantuma et al, 2000a;Heessen et al, 2002). Fusions of the GAr to GFP-based reporters that are targeted for degradation with different efficiencies (Dantuma et al, 2000b) showed that the GAr counteracts the degradation signal in a length-dependent manner (Dantuma et al, 2000a).…”

Section: The Rescue Program: Lmp-2a and The Capture Of Cellular Ubiqumentioning

confidence: 99%

“…It was found that the activity of the GAr is independent of its location in the target protein (Levitskaya et al, 1997;Sharipo et al, 1998;Dantuma et al, 2000a;Heessen et al, 2002) and is not restricted by the type of ubiquitin ligase involved in substrate modification (Sharipo et al, 1998;Dantuma et al, 2000a;Heessen et al, 2002). Fusions of the GAr to GFP-based reporters that are targeted for degradation with different efficiencies (Dantuma et al, 2000b) showed that the GAr counteracts the degradation signal in a length-dependent manner (Dantuma et al, 2000a). Indeed, EBNA-1 itself could be targeted for ubiquitin-dependent proteolysis using a strong degradation signal (Dantuma et al, 2000a).…”

Section: The Rescue Program: Lmp-2a and The Capture Of Cellular Ubiqumentioning

confidence: 99%

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Epstein–Barr virus oncogenesis and the ubiquitin–proteasome system

Masucci

2004

Oncogene

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Epstein-Barr virus (EBV), a human herpesvirus associated with lymphoid and epithelial cell tumors, encodes several proteins that exploit the ubiquitin-proteasome system to regulate latency and allow the persistence of infected cells in immunocompetent hosts. Further modifications of ubiquitin-dependent proteolysis by activated cellular oncogenes contribute to malignant transformation. A detailed understanding of these processes may lead to the development of new therapeutic strategies for EBVassociated cancers.

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Section: The Rescue Program: Lmp-2a and The Capture Of Cellular Ubiqumentioning

confidence: 99%

Section: The Rescue Program: Lmp-2a and The Capture Of Cellular Ubiqumentioning

confidence: 99%

Section: The Rescue Program: Lmp-2a and The Capture Of Cellular Ubiqumentioning

confidence: 99%

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Epstein–Barr virus oncogenesis and the ubiquitin–proteasome system

Masucci

2004

Oncogene

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“…41 However, the effect of these peptides on antigen presentation was not determined. 42,43 Subsequent studies have shown that cotranslational ubiquitination of EBNA-1 can override the GArmediated inhibition of proteasomal degradation and restore the endogenous processing and presentation of MHC class I-restricted CTL epitopes. 44 This suggests that the GAr domain not only prevents proteasomal degradation but also ubiquitination of GAr domain-containing proteins.…”

Section: Discussionmentioning

confidence: 99%

Creation of immune ‘stealth’ genes for gene therapy through fusion with the Gly-Ala repeat of EBNA-1

et al. 2003

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A major obstacle in gene-therapy protocols is T-cellmediated destruction of transgene-expressing cells. Therefore new approaches are needed to prevent rapid clearance of transduced cells. We exploited the Gly-Ala repeat (GAr) domain of the Epstein-Barr virus nuclear antigen-1, since the GAr prevents cytotoxic T-lymphocyte-epitope generation. Here we show that three different enzymes (viz. the E. coli LacZ gene encoded b-galactosidase, firefly luciferase, and HSV1 thymidine kinase) fused with the GAr retained their function. Moreover, linking GAr with b-galactosidase successfully prevented recognition of GAr-LacZ-expressing cells by b-galactosidase-specific CTL. Nonetheless, vaccination with a GAr-LacZ adenovirus or with an allogeneic cell line expressing GAr-LacZ resulted in the induction of b-galspecific CTL. This demonstrates that the GAr domain does not inhibit crosspresentation of antigens, but only affects breakdown of endogenously synthesized proteins. These data demonstrate how the GAr domain can be exploited to create immuno'stealth' genes by hiding transgene products from CTL-mediated immune attack.

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“…Nevertheless EBNA1 is a very attractive viral antigen for a therapeutic target due to its ubiquitous presence in all EBV infected cells, and novel strategies to avoid the restricted class I processing of EBNA1 have been reported by several groups. In the experiment of Tellam and his collegues, the EBNA1 gene was covalently linked with ubiquitin, and subject to targeting to the N-end rule pathway, in which the stability level of a protein in vivo can be dramatically changed by the identity of its N-terminal residue (Varshavsky, 1996;Tobery and Siliciano, 1999;Dantuma et al, 2000). These modifi cations dramatically enhanced intracellular degradation of the protein and restored CD8+ T cell recognition, demonstrating that GAr-mediated proteosomal blockade on EBNA1 can be reversed (Tellam et al, 2001).…”

Section: Ebna1mentioning

confidence: 99%

Epstein-Barr Virus-Associated Classical Hodgkin Lymphoma and Its Therapeutic Strategies

Lee¹

2011

Biomolecules and Therapeutics

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Lymphoma is a type of cancer involving cells of the immune system, and has two major categories: Hodgkin lymphoma (HL) and all other lymphomas (non-HL). Although the two types may display the same symptoms, they are readily distinguishable via microscopic examination, and differ in the way they develop, spread and are treated. HL is a unique clinicopathological disorder characterized by the rare presence of malignant cells (usually accounting for 0.1% to 10% of the cells in the total tumor mass) in a background of a nonneoplastic cellular microenvironment comprising T-and Blymphocytes and other cell types (Weiss et al., 1999). In the United States, about 8,500 new cases of HL were expected to be diagnosed in 2010, and the overall incidence is increasing each year (Maggioncalda et al., 2011).Although the pathogenesis of HL is still largely unknown, the association of HL with Epstein-Barr virus (EBV) infection has been demonstrated in many reports. For examples, HL patients show elevated antibody titers to EBV antigens (Levine et al., 1971), and the risk of developing HL is increased up to three-fold in population that have experienced infectious mononucleosis caused by primary EBV infection (Gutensohn Over the past few decades, our understanding of the epidemiology and immunopathogenesis of Hodgkin lymphoma (HL) has made enormous advances. Consequently, the treatment of HL has changed signifi cantly, rendering this disease of the most curable human cancers. To date, about 80% of patients achieve long-term disease-free survival. However, therapeutic challenges still remain, particularly regarding the salvage strategies for relapsed and refractory disease, which need further identifi cation of better prognostic markers and novel therapeutic schemes. Although the precise molecular mechanism by which Epstein-Barr virus (EBV) contributes to the generation of malignant cells present in HL still remains unknown, current increasing data on the role of EBV in the pathobiology of HL have encouraged people to start developing novel and specifi c therapeutic strategies for EBVassociated HL. This review will provide an overview of therapeutic approaches for acute EBV infection and the classical form of HL (cHL), especially focusing on EBV-associated HL cases. and Cole, 1980), and EBV DNA/RNA can be detected in HL tissues (Brink et al., 1997), suggesting that as a primary event in the development of this disease, EBV infection may play a very crucial role in the pathogenesis of HL. AbstractAccording to a population-based cohort study, the frequency of EBV associated HL among total HL cases varies from 30 to 50% (in certain cases even higher; >90% in developing and underdeveloped countries, and >95% in HIV associated cases), and most of them appear in classical Hodgkin lymphoma (cHL), the major type of HL (Herbst et al., 1991;Pallesen et al., 1991;Ambinder et al., 1993;Leoncini et al., 1996). Since EBV is an oncogenic virus that is able to subvert cellular processes supporting growth and survival, the approach to unravel the f...

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Inhibition of proteasomal degradation by the Gly-Ala repeat of Epstein–Barr virus is influenced by the length of the repeat and the strength of the degradation signal

Cited by 77 publications

References 25 publications

Epstein–Barr virus oncogenesis and the ubiquitin–proteasome system

Epstein–Barr virus oncogenesis and the ubiquitin–proteasome system

Creation of immune ‘stealth’ genes for gene therapy through fusion with the Gly-Ala repeat of EBNA-1

Epstein-Barr Virus-Associated Classical Hodgkin Lymphoma and Its Therapeutic Strategies

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