Nuclear Egress of Herpesviruses: The Prototypic Vesicular Nucleocytoplasmic Transport

Herpesvirus particles mature in two different cellular compartments. While capsid assembly and packaging of the genomic linear double-stranded DNA occur in the nucleus, virion formation takes place in the cytoplasm by the addition of numerous tegument proteins as well as acquisition of the viral envelope by budding into cellular vesicles derived from the trans-Golgi network containing virally encoded glycoproteins. To gain access to the final maturation compartment, herpesvirus nucleocapsids have to cross a formidable barrier, the nuclear envelope (NE). Since the ca. 120 nm diameter capsids are unable to traverse via nuclear pores, herpesviruses employ a vesicular transport through both leaflets of the NE. This process involves proteins which support local dissolution of the nuclear lamina to allow access of capsids to the inner nuclear membrane (INM), drive vesicle formation from the INM and mediate inclusion of the capsid as well as scission of the capsid-containing vesicle (also designated as “primary virion”). Fusion of the vesicle membrane (i.e., the “primary envelope”) with the outer nuclear membrane subsequently results in release of the nucleocapsid into the cytoplasm for continuing virion morphogenesis. While this process has long been thought to be unique for herpesviruses, a similar pathway for nuclear egress of macromolecular complexes has recently been observed in Drosophila. Thus, herpesviruses may have coopted a hitherto unrecognized cellular mechanism of vesicle-mediated nucleocytoplasmic transport. This could have far reaching consequences for our understanding of cellular functions as again unraveled by the study of viruses.