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

Author:

Flores-Martínez Yulia Alejandra,Le-Trilling Vu Thuy KhanhORCID,Trilling MirkoORCID

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.

Funder

Deutsche Forschungsgemeinschaft

Kulturstiftung Essen

Stiftung Universitätsmedizin Essen

Conacyt

Publisher

MDPI AG

Subject

Virology,Infectious Diseases

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3