Journal
VIRUSES-BASEL
Volume 12, Issue 6, Pages -Publisher
MDPI
DOI: 10.3390/v12060683
Keywords
human cytomegalovirus (HCMV); nuclear egress complex (NEC); core NEC crystal structures; alpha-, beta-, gamma-herpesviral NECs; sequence coevolution; highly conserved structures; subfamily-specific binding properties; regulators of viral replication and pathogenicity; novel NEC-directed antivirals
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Funding
- Deutsche Forschungsgemeinschaft [MA 1289/11-1, MU 1477/10-1, MI 2143/21, EI 423/4-1]
- Johannes und Frieda Marohn-Stiftung [Alz/Iko-Hahn/2019]
- Bayerische Forschungsstiftung [DeeP-CMV/AP-5/MM]
- Deutscher Akademischer Austauschdienst [Kicuntod/91686964, DAAD-Go8/2017-18/MM-WDR]
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Herpesviruses uniquely express two essential nuclear egress-regulating proteins forming a heterodimeric nuclear egress complex (core NEC). These core NECs serve as hexameric lattice-structured platforms for capsid docking and recruit viral and cellular NEC-associated factors that jointly exert nuclear lamina as well as membrane-rearranging functions (multicomponent NEC). The regulation of nuclear egress has been profoundly analyzed for murine and human cytomegaloviruses (CMVs) on a mechanistic basis, followed by the description of core NEC crystal structures, first for HCMV, then HSV-1, PRV and EBV. Interestingly, the highly conserved structural domains of these proteins stand in contrast to a very limited sequence conservation of the key amino acids within core NEC-binding interfaces. Even more surprising, although a high functional consistency was found when regarding the basic role of NECs in nuclear egress, a clear specification was identified regarding the limited, subfamily-spanning binding properties of core NEC pairs and NEC multicomponent proteins. This review summarizes the evolving picture of the relationship between sequence coevolution, structural conservation and properties of NEC interaction, comparing HCMV to alpha-, beta- and gamma-herpesviruses. Since NECs represent substantially important elements of herpesviral replication that are considered as drug-accessible targets, their putative translational use for antiviral strategies is discussed.
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