Herpesvirus Nuclear Egress

Abstract

Herpesviruses assemble and package their genomes into capsids in the nucleus, but complete final assembly of the mature virion in the cell cytoplasm. This requires passage of the genome-containing capsid across the double-membrane nuclear envelope. Herpesviruses have evolved a mechanism that relies on a pair of conserved viral gene products to shuttle the capsids from the nucleus to the cytoplasm by way of envelopment and de-envelopment at the inner and outer nuclear membranes, respectively. This complex process requires orchestration of the activities of viral and cellular factors to alter the architecture of the nuclear membrane, select capsids at the appropriate stage for egress, and accomplish efficient membrane budding and fusion events. The last few years have seen major advances in our understanding of the membrane budding mechanism and helped clarify the roles of viral and cellular proteins in the other, more mysterious steps. Here, we summarize and place into context this recent research and, hopefully, clarify both the major advances and major gaps in our understanding.

Structural basis for capsid recruitment and coat formation during HSV-1 nuclear egress

“…The intrinsic ability of the NEC to deform and bud membranes and to oligomerize into a hexagonal coat is well established [reviewed in (Bigalke and Heldwein 2016, Mettenleiter 2016, Bigalke and Heldwein 2017, Roller and Baines 2017)]. However, it is unclear how the capsid triggers the formation of the NEC coat around it or how the NEC coat is anchored to the capsid.…”

“…All herpesviruses can establish lifelong, latent infections within the host, from which they can periodically reactivate, spreading to uninfected tissues and hosts and causing a number of ailments. When the virus actively replicates during a primary infection or reactivation of a latent infection, the progeny virions are assembled and released from the cell in a process termed egress whereby herpesvirus capsids traverse cellular membranes twice [reviewed in (Johnson and Baines 2011, Bigalke and Heldwein 2016, Roller and Baines 2017)]. First, nuclear capsids bud at the inner nuclear membrane (INM) forming enveloped vesicles that pinch off into the perinuclear space.…”

Wash and the WASH Regulatory Complex function in Nuclear Envelope budding

“…Surprisingly, Wash's role in this process is bipotent and, independent of Recently, Nuclear Envelope (NE-) budding was identified as an alternative pathway for nuclear exit, particularly for large developmentally-required ribonucleoprotein (megaRNP) complexes that would otherwise need to unfold/remodel to fit through the NPCs (Fradkin and Budnik, 2016;Hatch and Hetzer, 2014;Hatch and Hetzer, 2012;Jokhi et al, 2013;Li et al, 2016;Parchure et al, 2017;Speese et al, 2012). In this pathway, large macromolecule complexes, such as megaRNPs, are encircled by the nuclear lamina (type-A and type-B lamins) and inner nuclear membrane, are pinched off from the inner nuclear membrane, cross the perinuclear space, fuse with the outer nuclear membrane, and release the megaRNPs into the cytoplasm (Figure 1A-C).Strikingly, NE-budding shares many features with the nuclear egress mechanism used by herpesviruses, common pathogens that cause and/or contribute to a diverse array of human diseases (Bigalke and Heldwein, 2016;Hagen et al, 2015;Lye et al, 2017;Mettenleiter et al, 2013;Parchure et al, 2017;Roller and Baines, 2017). As viruses often take advantage of preexisting host pathways for their livelihoods, the parallel between nuclear exit of herpesvirus nucleocapsids and that of megaRNPs suggests that NE-budding may be a general cellular mechanism that elegantly allows for the nuclear export of endogenous megaRNPs and/or other large cargos (cf.…”

“…As viruses often take advantage of preexisting host pathways for their livelihoods, the parallel between nuclear exit of herpesvirus nucleocapsids and that of megaRNPs suggests that NE-budding may be a general cellular mechanism that elegantly allows for the nuclear export of endogenous megaRNPs and/or other large cargos (cf. (Fradkin and Budnik, 2016;Mettenleiter et al, 2013;Parchure et al, 2017;Roller and Baines, 2017). Indeed, this pathway has also been implicated in the removal of obsolete macromolecular complexes or other material (i.e., large protein aggregates, polyubiquitylated proteins) from the nucleus (Jokhi et al, 2013;Ramaswami et al, 2013;Rose and Schlieker, 2012).The NE-budding pathway was first demonstrated in Drosophila synapse development, proving to be essential for neuromuscular junction integrity.…”

“…Strikingly, NE-budding shares many features with the nuclear egress mechanism used by herpesviruses, common pathogens that cause and/or contribute to a diverse array of human diseases (Bigalke and Heldwein, 2016;Hagen et al, 2015;Lye et al, 2017;Mettenleiter et al, 2013;Parchure et al, 2017;Roller and Baines, 2017). As viruses often take advantage of preexisting host pathways for their livelihoods, the parallel between nuclear exit of herpesvirus nucleocapsids and that of megaRNPs suggests that NE-budding may be a general cellular mechanism that elegantly allows for the nuclear export of endogenous megaRNPs and/or other large cargos (cf.…”