Nuclear Exodus: Herpesviruses Lead the Way

Abstract

Most DNA viruses replicate in the nucleus and exit it either by passing through the nuclear pores or by rupturing the nuclear envelope. Unusually, herpesviruses have evolved a complex mechanism of nuclear escape whereby nascent capsids bud at the inner nuclear membrane to form perinuclear virions that subsequently fuse with the outer nuclear membrane, releasing capsids into the cytosol. Although this general scheme is accepted in the field, the players and their roles are still debated. Recent studies illuminated critical mechanistic features of this enigmatic process and uncovered surprising parallels with a novel cellular nuclear export process. This review summarizes our current understanding of nuclear egress in herpesviruses, examines the experimental evidence and models, and outlines outstanding questions with the goal of stimulating new research in this area.

The human cytomegalovirus nuclear egress complex unites multiple functions: Recruitment of effectors, nuclear envelope rearrangement, and docking to nuclear capsids

“…This is depicted in detail in the left panels of Figure . In HSV‐1, 2 different types of ring‐ring contacts become obvious, ie, while one contact resembles the 2D lattice observed for HCMV, the second ring‐ring interaction differs slightly (right panels in Figure ). The most obvious differences concern the contacts formed between the core NEC heterodimers at the 2‐fold and 3‐fold rotational symmetry elements located at the boundaries between the ring‐like structures.…”

“…As a characteristic feature of herpesviruses, genomic replication starts in the host cell nucleus, where preformed capsids are packaged and exported to the cytoplasm for further virion maturation. The transition of capsids through the NE is a multistep regulatory process, termed nuclear egress . During this process, the NE is reorganized at specific sites with a profound importance of phosphorylation‐triggered distortion of the nuclear lamina .…”

“…The ultrastructural architecture of alpha‐herpesviral NEC hexagonal arrays was further investigated using a cell‐based system demonstrating the formation of perinuclear vesicles . Mechanistic details of how the core NEC induces membrane deformation, scission, and budding of membrane vesicles appear to be independent from further viral or cellular proteins (Figure B) …”

“…The core NEC sheet‐like structures exhibit a peculiar plane group symmetry characterized by the presence of 2‐, 3‐, and 6‐fold rotational symmetry elements (Figure ). However, as pointed out before by others, it is not possible to generate a perfectly regular polyhedron using simply a combination of these symmetry elements . A spherical coat displaying 6‐fold rotational symmetry elements can only be generated when 6‐fold symmetry elements are interspaced by 5‐fold symmetry elements.…”

Vesicular Nucleo-Cytoplasmic Transport—Herpesviruses as Pioneers in Cell Biology

“…It has become clear in the last decade that they leave the nucleus and traverse the nuclear envelope (NE) by a vesicle-mediated process that entails budding of nucleocapsids at the inner nuclear membrane (INM), thereby forming a primary enveloped virion in the perinuclear space. The primary envelope then fuses with the outer nuclear membrane (ONM) (recently reviewed in [2,3]). Long thought to be specific for herpesviruses, this pathway has recently also been suggested to function in the export of large ribonucleoprotein (RNP) complexes during development of Drosophila [4,5].…”