Virions of herpesviruses comprise capsid, tegument and envelope with embedded spikes built of glycoproteins. During morphogenesis, capsids are assembled in cell nuclei and filled with viral DNA before being transported to the nuclear periphery. From there, they either bud at the inner nuclear membrane into the perinuclear space acquiring envelope and tegument or else they gain access to the cytosol via an impaired nuclear envelope that starts by dilation of nuclear pores. Importantly, we cannot find hard evidence for the much-acclaimed process of “de-envelopment” of enveloped perinuclear virions via fusion with the outer nuclear membrane. Moreover, we challenge the logic seemingly supporting this pathway. Instead, we advocate a partially novel herpesvirus exit pathway: Enveloped perinuclear virions, which are protected against premature fusion, are released from the perinuclear space along the luminal continuum between perinuclear space, endoplasmic reticulum and Golgi complex where they are packaged into transport vacuoles. Tegumentation and envelopment occur at different entry sites. Accordingly, the first entry site is by budding at the inner nuclear membrane. Yet, the pathway is also accessible from the cytosolic side by budding of capsids, which escaped the nucleus via impaired nuclear envelope, either at the outer nuclear membrane or else further up throughout ER- and Golgi membranes. Alternatively, virions may acquire their envelope and tegument through the more complicated process designated wrapping, whereby capsids bud at Golgi membranes acquiring tegument and envelope simultaneously to enclosing themselves into a transport vacuole. Eventually, vacuoles carry virions to the cell periphery for exocytotic release, whereby vacuolar membranes of transport vacuoles fuse with the plasma membrane releasing virions into the extracellular space.
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