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Host and Viral Factors Involved in Nuclear Egress of Herpes Simplex Virus 1

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Host and Viral Factors Involved in Nuclear Egress of Herpes Simplex Virus 1 viruses Review Host and Viral Factors Involved in Nuclear Egress of Herpes Simplex Virus 1 Jun Arii Division of Clinical Virology, Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan; [email protected]; Tel.: +81-78-382-6272 Abstract: Herpes simplex virus 1 (HSV-1) replicates its genome and packages it into capsids within the nucleus. HSV-1 has evolved a complex mechanism of nuclear egress whereby nascent capsids bud on the inner nuclear membrane to form perinuclear virions that subsequently fuse with the outer nuclear membrane, releasing capsids into the cytosol. The viral-encoded nuclear egress complex (NEC) plays a crucial role in this vesicle-mediated nucleocytoplasmic transport. Nevertheless, similar system mediates the movement of other cellular macromolecular complexes in normal cells. Therefore, HSV-1 may utilize viral proteins to hijack the cellular machinery in order to facilitate capsid transport. However, little is known about the molecular mechanisms underlying this phenomenon. This review summarizes our current understanding of the cellular and viral factors involved in the nuclear egress of HSV-1 capsids. Keywords: herpesviruses; nuclear egress; primary envelopment; de-envelopment 1. Introduction The nuclear membrane (NM) consists of an inner nuclear membrane (INM) and an Citation: Arii, J. Host and Viral Factors Involved in Nuclear Egress of outer nuclear membrane (ONM), which separate nuclear and cytoplasmic activities in Herpes Simplex Virus 1. Viruses 2021, the eukaryotic cell (Figure1A). The segregation of the nucleoplasm from the cytoplasm 13, 754. https://doi.org/10.3390/ separates translation from transcription and maintains genome integrity. The INM and v13050754 ONM are biochemically distinct [1]. While the ONM is continuous and functionally interacts with the endoplasmic reticulum (ER), the INM contains its own set of integral Academic Editor: Donald M. Coen membrane proteins [2]. The ONM and the INM are separated by the perinuclear space and connected at annular junctions, where nuclear pore complexes (NPCs) are found. NPCs Received: 10 March 2021 are large macromolecular assemblies that form transport channels and regulate trafficking Accepted: 23 April 2021 between the cytoplasm and the nucleoplasm [3]. It had long been assumed that the NPC Published: 25 April 2021 was the only route out of the nucleus except during the early phases of mitosis when the nuclear envelope breaks down. Publisher’s Note: MDPI stays neutral Recently, however, an alternative and NPC-independent pathway for nuclear export with regard to jurisdictional claims in has been described in cells infected with viruses. Vesicle-mediated nucleocytoplasmic published maps and institutional affil- transport is a mechanism for the nuclear export of macromolecular complexes [4]. In this iations. system, a macromolecular complex in the nucleus buds through the INM to form a vesicle in the perinuclear space (‘primary envelopment’). This vesicle then fuses with the ONM to release the complex into the cytoplasm in a process called ‘de-envelopment’ [4] (Figure1B). This type of transport is observed in herpesvirus-infected mammalian cells and is required Copyright: © 2021 by the author. for the nuclear export of viral capsids that assemble in the nucleus [5]. Nucleocytoplasmic Licensee MDPI, Basel, Switzerland. transport (or ‘nuclear egress’) of capsids is essential for the life cycle of all herpesviruses, This article is an open access article as final maturation of their virions occurs in the cytoplasm. Although vesicle-mediated distributed under the terms and nucleocytoplasmic transport is not common in uninfected mammalian cells, it has been conditions of the Creative Commons reported that Drosophila cellular large ribonucleoprotein complexes (RNPs) utilize this Attribution (CC BY) license (https:// nuclear export mechanism in the absence of viral infection [6]. creativecommons.org/licenses/by/ 4.0/). Viruses 2021, 13, 754. https://doi.org/10.3390/v13050754 https://www.mdpi.com/journal/viruses Viruses 2021,, 13,, x 754 FOR PEER REVIEW 2 2of of 18 17 Figure 1. Overview of nuclear egress. (A) Illustration of a ‘normal’ nuclear envelope. INM, inner Figure 1. Overview of nuclear egress. (A) Illustration of a ‘normal’ nuclear envelope. INM, inner nuclearnuclear membrane; membrane; ONM, ONM, outer outer nuclear nuclear membrane; membrane; NPC, NPC, nuclear nuclear pore pore complex; complex; ER, ER, endoplasmic endoplasmic reticulum.reticulum. (B (B) Illustration) Illustration of ofvesicle-mediated vesicle-mediated nucleocytoplasmic nucleocytoplasmic transport. transport. A cargo A cargo (e.g., (e.g., viral viral capsid)capsid) in in the the nucleus nucleus buds buds throug throughh the the INM INM to toform form a vesicle a vesicle in inthe the perinuclear perinuclear space space that that then then fusesfuses with with the the ONM ONM to to release release the the comple complexx into into the the cytoplasm cytoplasm (de-envelopment). (de-envelopment). TheThe goal goal of of this this review review is isto topresent present the the current current knowledge knowledge of the of cellular the cellular factors factors that arethat involved are involved in vesicle-mediated in vesicle-mediated nucleocytoplas nucleocytoplasmicmic transport transport of herpesvirus of herpesvirus capsids. capsids. In particular,In particular, the review the review focuses focuses on herpes on herpes simplex simplex virus virus1 (HSV-1), 1 (HSV-1), which whichhas been has exten- been sivelyextensively studied studied and for and which for which the mechanisms the mechanisms of capsid of capsid nuclear nuclear egress egress are relatively are relatively well understood.well understood. The author The author hopes hopes that the that review the review will willstimulate stimulate researchers researchers in the in thefield field to engageto engage in new in new research research projects projects that that will will further further elucidate elucidate the the many many mysteries mysteries of of this this transporttransport system. system. 2. Overview of Nuclear Egress of Herpesviruses 2. Overview of Nuclear Egress of Herpesviruses Herpesviruses are enveloped double-stranded DNA viruses that establish lifelong Herpesviruses are enveloped double-stranded DNA viruses that establish lifelong latent infections in their natural hosts [7]. The Herpesviridae family is subdivided into the latent infections in their natural hosts [7]. The Herpesviridae family is subdivided into the Alphaherpesvirinae, Betaherpesvirinae, and Gammaherpesvirinae subfamilies, based on their Alphaherpesvirinae, Betaherpesvirinae, and Gammaherpesvirinae subfamilies, based on their molecular and biological properties [7]. HSV-1 is the prototype of the alphaherpesvirus molecular and biological properties [7]. HSV-1 is the prototype of the alphaherpesvirus subfamily, which is comprised of the most common pathogenic agents in humans, and subfamily,causes a variety which of is conditions comprised such of the as mucocutaneousmost common pathogenic disease, keratitis, agents skinin humans, disease and and causesencephalitis a variety [8]. of Herpesviruses conditions such share as amucocu commontaneous virion disease, structure keratitis, and similar skin proliferationdisease and encephalitisstrategies. A [8]. mature Herpesviruses virion consists share of a ancommo icosahedraln virion capsid structure with and a linear similar double-stranded proliferation strategies.DNA genome, A mature a proteinaceous virion consists layer of an called icosahedral tegument, capsid and with a host-membranea linear double-stranded derived DNAenvelope genome, spiked a proteinaceous with viral glycoproteins. layer called tegument, and a host-membrane derived en- velopeHerpesviruses spiked with viral replicate glycoproteins. their genomes and package them into capsids within the host cell nucleus.Herpesviruses These replicate capsids their must genomes traverse and from pa theckage nucleus them tointo the capsids cytoplasm within through the host a cellprocess nucleus. called These nuclear capsids egress. must In brief,traverse the nascentfrom the nucleocapsids nucleus to th bude cytoplasm at the INM through to form a processprimary called virions nuclear in the egress. perinuclear In brief, space, the andnascent then nucleocapsids the envelopes bud of primary at the INM virions to form fuse Viruses 2021, 13, 754 3 of 17 with the ONM, releasing the nucleocapsids into the cytoplasm for further maturation (Figure1B). In the cytoplasm, nucleocapsids bud into vesicles derived from trans-Golgi networks or endosomes in a process called ‘secondary envelopment’. Finally, enveloped virions are released from the cells through an exocytotic pathway [5]. This envelopment/de-envelopment model of herpesvirus egress is now generally accepted and appears to be the dominant mechanism employed by this virus. However, other routes have been proposed. For example, capsids may be transported concomitantly with nuclear envelope breakdown in certain situations [9]. It has also been reported that capsids may egress from the nucleus through defective nuclear pores [10,11]. 3. The Nuclear Egress Complex (NEC) The NEC is composed of the conserved viral proteins UL31 and UL34 and plays a crucial role in the nucleocytoplasmic transport of newly assembled nucleocapsids [5,12]. In the absence of either protein, capsids do not bud at the INM and instead accumulate inside the nucleus [13–18]. UL34
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