Abstract
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.
Highlights
Human cytomegalovirus (HCMV; Human betaherpesvirus 5 (HHV-5); Taxonomy ID (TaxID) 10359) is the prototypical member of the Betaherpesvirinae
To address if Nedd8-activating enzyme (NAE), the known target of MLN4924, is a bona fide host dependency factor (HDF) of mouse cytomegalovirus (MCMV) and HCMV or if MLN4924 might rather act against CMVs through yet unidentified NAE-independent effects, we were eager to test the potential antiviral effects of other NAE inhibitors
We demonstrate here that nanomolar concentrations of the NAE inhibitor TAS4464 stabilizes cullin RING ubiquitin ligases (CRL) substrates such as p21 and elicits significant and dose-dependent antiviral activity in different cells against mouse and human CMV
Summary
Human cytomegalovirus (HCMV; Human betaherpesvirus 5 (HHV-5); Taxonomy ID (TaxID) 10359) is the prototypical member of the Betaherpesvirinae. HCMV inevitably establishes lifelong latency from which it can reactivate once the host experiences episodes of stress and/or compromised immunity. HCMV infections often become life-threatening in persons with immature, compromised, or senescent immunity who frequently suffer from symptomatic diseases caused by HCMV replication. Due to the immature status of the developing immune system, HCMV can replicate in these infants, leading to acute diseases and long-term sequelae such as microcephaly, mental retardation, and sensorineural hearing loss [3]. HCMV is one of the most common perinatal infections in developed countries [4] and a major cause of deafness. Despite the high prevalence of childhood diseases caused by HCMV [5], there is insufficient awareness among women of childbearing age regarding the risks of congenital HCMV infections [6]
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