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Article

Nedd8-Activating Enzyme Is a Druggable Host Dependency Factor of Human and Mouse Cytomegalovirus

Institute for Virology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany
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Author to whom correspondence should be addressed.
Academic Editor: Elke Bogner
Viruses 2021, 13(8), 1610; https://doi.org/10.3390/v13081610
Received: 30 June 2021 / Revised: 10 August 2021 / Accepted: 11 August 2021 / Published: 14 August 2021
(This article belongs to the Special Issue New Concepts of Antiviral Strategies Against HCMV)
Human cytomegalovirus causes diseases in individuals with insufficient immunity. Cytomegaloviruses exploit the ubiquitin proteasome pathway to manipulate the proteome of infected cells. The proteasome degrades ubiquitinated proteins. The family of cullin RING ubiquitin ligases (CRL) regulates the stability of numerous important proteins. If the cullin within the CRL is modified with Nedd8 (“neddylated”), the CRL is enzymatically active, while CRLs lacking Nedd8 modifications are inactive. The Nedd8-activating enzyme (NAE) is indispensable for neddylation. By binding to NAE and inhibiting neddylation, the drug MLN4924 (pevonedistat) causes CRL inactivation and stabilization of CRL target proteins. We showed that MLN4924 elicits potent antiviral activity against cytomegaloviruses, suggesting that NAE might be a druggable host dependency factor (HDF). However, MLN4924 is a nucleoside analog related to AMP, and the antiviral activity of MLN4924 may have been influenced by off-target effects in addition to NAE inhibition. To test if NAE is indeed an HDF, we assessed the novel NAE inhibitor TAS4464 and observed potent antiviral activity against mouse and human cytomegalovirus. Additionally, we raised an MLN4924-resistant cell clone and showed that MLN4924 as well as TAS4464 lose their antiviral activity in these cells. Our results indicate that NAE, the neddylation process, and CRLs are druggable HDFs of cytomegaloviruses. View Full-Text
Keywords: human cytomegalovirus (HCMV); Murid herpesvirus 1 (MuHV-1); mouse cytomegalovirus (MCMV); nedd8; nedd8-activating enzyme (NAE); cullin RING ubiquitin ligase (CRL); ubiquitination; host dependency factor; TAS4464; MLN4924 human cytomegalovirus (HCMV); Murid herpesvirus 1 (MuHV-1); mouse cytomegalovirus (MCMV); nedd8; nedd8-activating enzyme (NAE); cullin RING ubiquitin ligase (CRL); ubiquitination; host dependency factor; TAS4464; MLN4924
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MDPI and ACS Style

Flores-Martínez, Y.A.; Le-Trilling, V.T.K.; Trilling, M. Nedd8-Activating Enzyme Is a Druggable Host Dependency Factor of Human and Mouse Cytomegalovirus. Viruses 2021, 13, 1610. https://doi.org/10.3390/v13081610

AMA Style

Flores-Martínez YA, Le-Trilling VTK, Trilling M. Nedd8-Activating Enzyme Is a Druggable Host Dependency Factor of Human and Mouse Cytomegalovirus. Viruses. 2021; 13(8):1610. https://doi.org/10.3390/v13081610

Chicago/Turabian Style

Flores-Martínez, Yulia A., Vu T.K. Le-Trilling, and Mirko Trilling. 2021. "Nedd8-Activating Enzyme Is a Druggable Host Dependency Factor of Human and Mouse Cytomegalovirus" Viruses 13, no. 8: 1610. https://doi.org/10.3390/v13081610

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