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NEDDylation is essential for Kaposi’s sarcoma-associated herpesvirus latency and lytic reactivation and represents a novel anti-KSHV target
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dc.contributor.author | Hughes, David John | |
dc.contributor.author | Wood, Jennifer J | |
dc.contributor.author | Jackson, Brian R | |
dc.contributor.author | Baquero-Pérez, Belinda | |
dc.contributor.author | Whitehouse, Adrian | |
dc.date.accessioned | 2015-03-24T11:01:02Z | |
dc.date.available | 2015-03-24T11:01:02Z | |
dc.date.issued | 2015-03-20 | |
dc.identifier | 172315204 | |
dc.identifier | c4f3fd97-d878-4576-865f-391b817ecafc | |
dc.identifier | 84926429511 | |
dc.identifier | 000352201900077 | |
dc.identifier.citation | Hughes , D J , Wood , J J , Jackson , B R , Baquero-Pérez , B & Whitehouse , A 2015 , ' NEDDylation is essential for Kaposi’s sarcoma-associated herpesvirus latency and lytic reactivation and represents a novel anti-KSHV target ' , PLoS Pathogens , vol. 11 , no. 3 , e1004771 . https://doi.org/10.1371/journal.ppat.1004771 | en |
dc.identifier.issn | 1553-7366 | |
dc.identifier.other | ORCID: /0000-0002-0090-5710/work/39632379 | |
dc.identifier.uri | https://hdl.handle.net/10023/6296 | |
dc.description | This work was funded in parts by The Wellcome Trust (http://www.wellcome.ac.uk), Yorkshire Cancer Research (http://yorkshirecancerresearch.org.uk) and the BBSRC (http://www.bbsrc.ac.uk, grant number BB/K000306/1. | en |
dc.description.abstract | Kaposi’s sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL), which are aggressive malignancies associated with immunocompromised patients. For many non-viral malignancies, therapeutically targeting the ubiquitin proteasome system (UPS) has been successful. Likewise, laboratory studies have demonstrated that inhibition of the UPS might provide a promising avenue for the treatment of KSHV-associated diseases. The largest class of E3 ubiquitin ligases are the cullin-RING ligases (CRLs) that are activated by an additional ubiquitin-like protein, NEDD8. We show that pharmacological inhibition of NEDDylation (using the small molecule inhibitor MLN4924) is cytotoxic to PEL cells by inhibiting NF-κB. We also show that CRL4B is a novel regulator of latency as its inhibition reactivated lytic gene expression. Furthermore, we uncovered a requirement for NEDDylation during the reactivation of the KSHV lytic cycle. Intriguingly, inhibition prevented viral DNA replication but not lytic cycle-associated gene expression, highlighting a novel mechanism that uncouples these two features of KSHV biology. Mechanistically, we show that MLN4924 treatment precluded the recruitment of the viral pre-replication complex to the origin of lytic DNA replication (OriLyt). These new findings have revealed novel mechanisms that regulate KSHV latency and reactivation. Moreover, they demonstrate that inhibition of NEDDylation represents a novel approach for the treatment of KSHV-associated malignancies. | |
dc.format.extent | 26 | |
dc.format.extent | 1353224 | |
dc.language.iso | eng | |
dc.relation.ispartof | PLoS Pathogens | en |
dc.subject | KSHV | en |
dc.subject | NEDD8 | en |
dc.subject | NEDDylation | en |
dc.subject | Ubiquitin proteasome system | en |
dc.subject | Cullin-RING ligase | en |
dc.subject | QH301 Biology | en |
dc.subject | NDAS | en |
dc.subject | BDC | en |
dc.subject | R2C | en |
dc.subject.lcc | QH301 | en |
dc.title | NEDDylation is essential for Kaposi’s sarcoma-associated herpesvirus latency and lytic reactivation and represents a novel anti-KSHV target | en |
dc.type | Journal article | en |
dc.contributor.institution | University of St Andrews. School of Biology | en |
dc.contributor.institution | University of St Andrews. Biomedical Sciences Research Complex | en |
dc.identifier.doi | 10.1371/journal.ppat.1004771 | |
dc.description.status | Peer reviewed | en |
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