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Abstract

Herpesvirus nucleocapsids are assembled in the nucleus but mature to infectious virions in the cytosol. To gain access to the maturation compartment intranuclear capsids have to cross the nuclear envelope (NE). While nucleo-cytoplasmic transport usually occurs through nuclear pore complexes (NPC), the ca. 120 nm capsids are too large to pass through NPC. Thus, herpesviruses use a vesicle-mediated nucleo-cytoplasmic transport by budding of nucleocapsids at the inner nuclear membrane thereby obtaining a primary envelope, which then fuses with the outer nuclear membrane to release the capsid into the cytosol. Nuclear egress is mediated by the heterodimeric viral nuclear egress complex (NEC) which alone is sufficient for membrane bending and scission in artificial membrane systems as well as authentic nuclear envelopes. We have analyzed vesicle formation by the NEC in situ by multimodal imaging and determined the crystal structure of the NEC of the alphaherpesvirus pseudorabies virus. Our data unravel basic principles of vesiculation from the INM including the formation of two hexagonal lattices composed of multiple copies of the NEC which induce bending of the INM resulting in the formation of vesicles of distinct size capable to accommodate the viral nucleocapsid for transport. Although this herpesvirus-induced vesicular transfer through the NE has been thought unique, it may actually also be used for transport of other large cellular cargo, e.g. RNP complexes, through the NE.