- home
- Advanced Search
- COVID-19
- Open Access
- Publications
- Article
- Natural Sciences and Engineering Re...
- SILVER
- CA
- COVID-19
- Open Access
- Publications
- Article
- Natural Sciences and Engineering Re...
- SILVER
- CA
Loading
description Publicationkeyboard_double_arrow_right Article 2014 NetherlandsPublisher:Public Library of Science (PLoS) Funded by:NSERC, NWO | Nidovirus deubiquitinatin..., EC | SILVERNSERC ,NWO| Nidovirus deubiquitinating proteases: viral double edged swords ,EC| SILVERBailey-Elkin, B.A.; Kasteren, P.B. van; Snijder, E.J.; Kikkert, M.; Mark, B.L.;Recent studies have revealed that proteases encoded by three very diverse RNA virus groups share structural similarity with enzymes of the Ovarian Tumor (OTU) superfamily of deubiquitinases (DUBs). The publication of the latest of these reports in quick succession prevented proper recognition and discussion of the shared features of these viral enzymes. Here we provide a brief structural and functional comparison of these virus-encoded OTU DUBs. Interestingly, although their shared structural features and substrate specificity tentatively place them within the same protease superfamily, they also show interesting differences that trigger speculation as to their origins.
Europe PubMed Centra... arrow_drop_down Europe PubMed CentralArticle . 2014Full-Text: http://europepmc.org/articles/PMC3968130Data sources: PubMed Centraladd ClaimPlease grant OpenAIRE to access and update your ORCID works.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.All Research productsarrow_drop_down <script type="text/javascript"> <!-- document.write('<div id="oa_widget"></div>'); document.write('<script type="text/javascript" src="https://www.openaire.eu/index.php?option=com_openaire&view=widget&format=raw&projectId=10.1371/journal.ppat.1003894&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.euAccess RoutesGreen gold 33 citations 33 popularity Top 10% influence Average impulse Top 10% Powered by BIP!more_vert Europe PubMed Centra... arrow_drop_down Europe PubMed CentralArticle . 2014Full-Text: http://europepmc.org/articles/PMC3968130Data sources: PubMed Centraladd ClaimPlease grant OpenAIRE to access and update your ORCID works.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.All Research productsarrow_drop_down <script type="text/javascript"> <!-- document.write('<div id="oa_widget"></div>'); document.write('<script type="text/javascript" src="https://www.openaire.eu/index.php?option=com_openaire&view=widget&format=raw&projectId=10.1371/journal.ppat.1003894&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.eudescription Publicationkeyboard_double_arrow_right Other literature type , Article 2014 NetherlandsPublisher:Elsevier BV Funded by:NSERC, NWO | Nidovirus deubiquitinatin..., CIHR +1 projectsNSERC ,NWO| Nidovirus deubiquitinating proteases: viral double edged swords ,CIHR ,EC| SILVERBailey-Elkin, B.A.; Knaap, R.C.M.; Johnson, G.G.; Dalebout, T.J.; Ninaber, D.K.; Kasteren, P.B. van; Bredenbeek, P.J.; Snijder, E.J.; Kikkert, M.; Mark, B.L.;Middle East respiratory syndrome coronavirus (MERS-CoV) is a newly emerging human pathogen that was first isolated in 2012. MERS-CoV replication depends in part on a virus-encoded papain-like protease (PL(pro)) that cleaves the viral replicase polyproteins at three sites releasing non-structural protein 1 (nsp1), nsp2, and nsp3. In addition to this replicative function, MERS-CoV PL(pro) was recently shown to be a deubiquitinating enzyme (DUB) and to possess deISGylating activity, as previously reported for other coronaviral PL(pro) domains, including that of severe acute respiratory syndrome coronavirus. These activities have been suggested to suppress host antiviral responses during infection. To understand the molecular basis for ubiquitin (Ub) recognition and deconjugation by MERS-CoV PL(pro), we determined its crystal structure in complex with Ub. Guided by this structure, mutations were introduced into PL(pro) to specifically disrupt Ub binding without affecting viral polyprotein cleavage, as determined using an in trans nsp3↓4 cleavage assay. Having developed a strategy to selectively disable PL(pro) DUB activity, we were able to specifically examine the effects of this activity on the innate immune response. Whereas the wild-type PL(pro) domain was found to suppress IFN-β promoter activation, PL(pro) variants specifically lacking DUB activity were no longer able to do so. These findings directly implicate the DUB function of PL(pro), and not its proteolytic activity per se, in the inhibition of IFN-β promoter activity. The ability to decouple the DUB activity of PL(pro) from its role in viral polyprotein processing now provides an approach to further dissect the role(s) of PL(pro) as a viral DUB during MERS-CoV infection.
Journal of Biologica... arrow_drop_down https://doi.org/10.1074/jbc.M1...Other literature typeData sources: European Union Open Data Portaladd ClaimPlease grant OpenAIRE to access and update your ORCID works.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.All Research productsarrow_drop_down <script type="text/javascript"> <!-- document.write('<div id="oa_widget"></div>'); document.write('<script type="text/javascript" src="https://www.openaire.eu/index.php?option=com_openaire&view=widget&format=raw&projectId=10.1074/jbc.m114.609644&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.euAccess RoutesGreen gold 130 citations 130 popularity Top 1% influence Top 10% impulse Top 1% Powered by BIP!more_vert Journal of Biologica... arrow_drop_down https://doi.org/10.1074/jbc.M1...Other literature typeData sources: European Union Open Data Portaladd ClaimPlease grant OpenAIRE to access and update your ORCID works.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.All Research productsarrow_drop_down <script type="text/javascript"> <!-- document.write('<div id="oa_widget"></div>'); document.write('<script type="text/javascript" src="https://www.openaire.eu/index.php?option=com_openaire&view=widget&format=raw&projectId=10.1074/jbc.m114.609644&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.eudescription Publicationkeyboard_double_arrow_right Article , Other literature type 2013 NetherlandsPublisher:Proceedings of the National Academy of Sciences Funded by:NSERC, NWO | Nidovirus deubiquitinatin..., EC | SILVER +1 projectsNSERC ,NWO| Nidovirus deubiquitinating proteases: viral double edged swords ,EC| SILVER ,CIHRKasteren, P.B. van; Bailey-Elkin, B.A.; James, T.W.; Ninaber, D.K.; Beugeling, C.; Khajehpour, M.; Snijder, E.J.; Mark, B.L.; Kikkert, M.;Protein ubiquitination regulates important innate immune responses. The discovery of viruses encoding deubiquitinating enzymes (DUBs) suggests they remove ubiquitin to evade ubiquitin-dependent antiviral responses; however, this has never been conclusively demonstrated in virus-infected cells. Arteriviruses are economically important positive-stranded RNA viruses that encode an ovarian tumor (OTU) domain DUB known as papain-like protease 2 (PLP2). This enzyme is essential for arterivirus replication by cleaving a site within the viral replicase polyproteins and also removes ubiquitin from cellular proteins. To dissect this dual specificity, which relies on a single catalytic site, we determined the crystal structure of equine arteritis virus PLP2 in complex with ubiquitin (1.45 Å). PLP2 binds ubiquitin using a zinc finger that is uniquely integrated into an exceptionally compact OTU-domain fold that represents a new subclass of zinc-dependent OTU DUBs. Notably, the ubiquitin-binding surface is distant from the catalytic site, which allowed us to mutate this surface to significantly reduce DUB activity without affecting polyprotein cleavage. Viruses harboring such mutations exhibited WT replication kinetics, confirming that PLP2-mediated polyprotein cleavage was intact, but the loss of DUB activity strikingly enhanced innate immune signaling. Compared with WT virus infection, IFN-β mRNA levels in equine cells infected with PLP2 mutants were increased by nearly an order of magnitude. Our findings not only establish PLP2 DUB activity as a critical factor in arteriviral innate immune evasion, but the selective inactivation of DUB activity also opens unique possibilities for developing improved live attenuated vaccines against arteriviruses and other viruses encoding similar dual-specificity proteases.
Proceedings of the N... arrow_drop_down add ClaimPlease grant OpenAIRE to access and update your ORCID works.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.All Research productsarrow_drop_down <script type="text/javascript"> <!-- document.write('<div id="oa_widget"></div>'); document.write('<script type="text/javascript" src="https://www.openaire.eu/index.php?option=com_openaire&view=widget&format=raw&projectId=10.1073/pnas.1218464110&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.euAccess RoutesGreen bronze 109 citations 109 popularity Top 10% influence Top 10% impulse Top 1% Powered by BIP!more_vert Proceedings of the N... arrow_drop_down add ClaimPlease grant OpenAIRE to access and update your ORCID works.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.All Research productsarrow_drop_down <script type="text/javascript"> <!-- document.write('<div id="oa_widget"></div>'); document.write('<script type="text/javascript" src="https://www.openaire.eu/index.php?option=com_openaire&view=widget&format=raw&projectId=10.1073/pnas.1218464110&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.eu
Loading
description Publicationkeyboard_double_arrow_right Article 2014 NetherlandsPublisher:Public Library of Science (PLoS) Funded by:NSERC, NWO | Nidovirus deubiquitinatin..., EC | SILVERNSERC ,NWO| Nidovirus deubiquitinating proteases: viral double edged swords ,EC| SILVERBailey-Elkin, B.A.; Kasteren, P.B. van; Snijder, E.J.; Kikkert, M.; Mark, B.L.;Recent studies have revealed that proteases encoded by three very diverse RNA virus groups share structural similarity with enzymes of the Ovarian Tumor (OTU) superfamily of deubiquitinases (DUBs). The publication of the latest of these reports in quick succession prevented proper recognition and discussion of the shared features of these viral enzymes. Here we provide a brief structural and functional comparison of these virus-encoded OTU DUBs. Interestingly, although their shared structural features and substrate specificity tentatively place them within the same protease superfamily, they also show interesting differences that trigger speculation as to their origins.
Europe PubMed Centra... arrow_drop_down Europe PubMed CentralArticle . 2014Full-Text: http://europepmc.org/articles/PMC3968130Data sources: PubMed Centraladd ClaimPlease grant OpenAIRE to access and update your ORCID works.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.All Research productsarrow_drop_down <script type="text/javascript"> <!-- document.write('<div id="oa_widget"></div>'); document.write('<script type="text/javascript" src="https://www.openaire.eu/index.php?option=com_openaire&view=widget&format=raw&projectId=10.1371/journal.ppat.1003894&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.euAccess RoutesGreen gold 33 citations 33 popularity Top 10% influence Average impulse Top 10% Powered by BIP!more_vert Europe PubMed Centra... arrow_drop_down Europe PubMed CentralArticle . 2014Full-Text: http://europepmc.org/articles/PMC3968130Data sources: PubMed Centraladd ClaimPlease grant OpenAIRE to access and update your ORCID works.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.All Research productsarrow_drop_down <script type="text/javascript"> <!-- document.write('<div id="oa_widget"></div>'); document.write('<script type="text/javascript" src="https://www.openaire.eu/index.php?option=com_openaire&view=widget&format=raw&projectId=10.1371/journal.ppat.1003894&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.eudescription Publicationkeyboard_double_arrow_right Other literature type , Article 2014 NetherlandsPublisher:Elsevier BV Funded by:NSERC, NWO | Nidovirus deubiquitinatin..., CIHR +1 projectsNSERC ,NWO| Nidovirus deubiquitinating proteases: viral double edged swords ,CIHR ,EC| SILVERBailey-Elkin, B.A.; Knaap, R.C.M.; Johnson, G.G.; Dalebout, T.J.; Ninaber, D.K.; Kasteren, P.B. van; Bredenbeek, P.J.; Snijder, E.J.; Kikkert, M.; Mark, B.L.;Middle East respiratory syndrome coronavirus (MERS-CoV) is a newly emerging human pathogen that was first isolated in 2012. MERS-CoV replication depends in part on a virus-encoded papain-like protease (PL(pro)) that cleaves the viral replicase polyproteins at three sites releasing non-structural protein 1 (nsp1), nsp2, and nsp3. In addition to this replicative function, MERS-CoV PL(pro) was recently shown to be a deubiquitinating enzyme (DUB) and to possess deISGylating activity, as previously reported for other coronaviral PL(pro) domains, including that of severe acute respiratory syndrome coronavirus. These activities have been suggested to suppress host antiviral responses during infection. To understand the molecular basis for ubiquitin (Ub) recognition and deconjugation by MERS-CoV PL(pro), we determined its crystal structure in complex with Ub. Guided by this structure, mutations were introduced into PL(pro) to specifically disrupt Ub binding without affecting viral polyprotein cleavage, as determined using an in trans nsp3↓4 cleavage assay. Having developed a strategy to selectively disable PL(pro) DUB activity, we were able to specifically examine the effects of this activity on the innate immune response. Whereas the wild-type PL(pro) domain was found to suppress IFN-β promoter activation, PL(pro) variants specifically lacking DUB activity were no longer able to do so. These findings directly implicate the DUB function of PL(pro), and not its proteolytic activity per se, in the inhibition of IFN-β promoter activity. The ability to decouple the DUB activity of PL(pro) from its role in viral polyprotein processing now provides an approach to further dissect the role(s) of PL(pro) as a viral DUB during MERS-CoV infection.
Journal of Biologica... arrow_drop_down https://doi.org/10.1074/jbc.M1...Other literature typeData sources: European Union Open Data Portaladd ClaimPlease grant OpenAIRE to access and update your ORCID works.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.All Research productsarrow_drop_down <script type="text/javascript"> <!-- document.write('<div id="oa_widget"></div>'); document.write('<script type="text/javascript" src="https://www.openaire.eu/index.php?option=com_openaire&view=widget&format=raw&projectId=10.1074/jbc.m114.609644&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.euAccess RoutesGreen gold 130 citations 130 popularity Top 1% influence Top 10% impulse Top 1% Powered by BIP!more_vert Journal of Biologica... arrow_drop_down https://doi.org/10.1074/jbc.M1...Other literature typeData sources: European Union Open Data Portaladd ClaimPlease grant OpenAIRE to access and update your ORCID works.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.All Research productsarrow_drop_down <script type="text/javascript"> <!-- document.write('<div id="oa_widget"></div>'); document.write('<script type="text/javascript" src="https://www.openaire.eu/index.php?option=com_openaire&view=widget&format=raw&projectId=10.1074/jbc.m114.609644&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.eudescription Publicationkeyboard_double_arrow_right Article , Other literature type 2013 NetherlandsPublisher:Proceedings of the National Academy of Sciences Funded by:NSERC, NWO | Nidovirus deubiquitinatin..., EC | SILVER +1 projectsNSERC ,NWO| Nidovirus deubiquitinating proteases: viral double edged swords ,EC| SILVER ,CIHRKasteren, P.B. van; Bailey-Elkin, B.A.; James, T.W.; Ninaber, D.K.; Beugeling, C.; Khajehpour, M.; Snijder, E.J.; Mark, B.L.; Kikkert, M.;Protein ubiquitination regulates important innate immune responses. The discovery of viruses encoding deubiquitinating enzymes (DUBs) suggests they remove ubiquitin to evade ubiquitin-dependent antiviral responses; however, this has never been conclusively demonstrated in virus-infected cells. Arteriviruses are economically important positive-stranded RNA viruses that encode an ovarian tumor (OTU) domain DUB known as papain-like protease 2 (PLP2). This enzyme is essential for arterivirus replication by cleaving a site within the viral replicase polyproteins and also removes ubiquitin from cellular proteins. To dissect this dual specificity, which relies on a single catalytic site, we determined the crystal structure of equine arteritis virus PLP2 in complex with ubiquitin (1.45 Å). PLP2 binds ubiquitin using a zinc finger that is uniquely integrated into an exceptionally compact OTU-domain fold that represents a new subclass of zinc-dependent OTU DUBs. Notably, the ubiquitin-binding surface is distant from the catalytic site, which allowed us to mutate this surface to significantly reduce DUB activity without affecting polyprotein cleavage. Viruses harboring such mutations exhibited WT replication kinetics, confirming that PLP2-mediated polyprotein cleavage was intact, but the loss of DUB activity strikingly enhanced innate immune signaling. Compared with WT virus infection, IFN-β mRNA levels in equine cells infected with PLP2 mutants were increased by nearly an order of magnitude. Our findings not only establish PLP2 DUB activity as a critical factor in arteriviral innate immune evasion, but the selective inactivation of DUB activity also opens unique possibilities for developing improved live attenuated vaccines against arteriviruses and other viruses encoding similar dual-specificity proteases.
Proceedings of the N... arrow_drop_down add ClaimPlease grant OpenAIRE to access and update your ORCID works.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.All Research productsarrow_drop_down <script type="text/javascript"> <!-- document.write('<div id="oa_widget"></div>'); document.write('<script type="text/javascript" src="https://www.openaire.eu/index.php?option=com_openaire&view=widget&format=raw&projectId=10.1073/pnas.1218464110&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.euAccess RoutesGreen bronze 109 citations 109 popularity Top 10% influence Top 10% impulse Top 1% Powered by BIP!more_vert Proceedings of the N... arrow_drop_down add ClaimPlease grant OpenAIRE to access and update your ORCID works.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.All Research productsarrow_drop_down <script type="text/javascript"> <!-- document.write('<div id="oa_widget"></div>'); document.write('<script type="text/javascript" src="https://www.openaire.eu/index.php?option=com_openaire&view=widget&format=raw&projectId=10.1073/pnas.1218464110&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.eu