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Viruses and Nuclear Egress

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A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Animal Viruses".

Deadline for manuscript submissions: closed (31 August 2021) | Viewed by 33020

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Special Issue Editor

Prof. Dr. Donald M. Coen

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Guest Editor

Harvard Medical School, Boston, United States
Interests: post-transcriptional regulation of gene expression relevant to virus latency; structure and function of viral DNA replication proteins; nuclear egress; and antiviral drug targets, drug mechanisms, and drug resistance

Special Issue Information

Dear Colleagues,

Virus nucleocapsids that assemble in the nucleus need a way to get into the cytoplasm. This fascinating process, known as nuclear egress, has been most deeply explored for herpesviruses. Herpesvirus nuclear egress includes movement of nucleocapsids to the nuclear periphery, disruption of the nuclear lamina, budding through the inner nuclear membrane, and fusion of the resulting enveloped particles with the outer nuclear membrane. Studies of nuclear egress can shed light on host cell nuclear functions, and abet discovery and understanding of antiviral drugs. Great strides have been made over the last two decades in understanding herpesvirus nuclear egress. Nevertheless, much remains to be learned regarding each of the steps of this process, and similar processes in other systems.

In this Special issue of Viruses, we seek research papers that contribute to our knowledge of nuclear egress and the viral and host proteins involved in this process in any virus or cellular system, or that communicate the discovery or understanding of antiviral compounds that target nuclear egress.

Prof. Dr. Donald M. Coen
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Viruses is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

nuclear egress
herpesviruses
nucleocapsids
intranuclear movement
nuclear lamina
nuclear membranes
budding
envelope fusion
antiviral drugs
protein kinases

Published Papers (12 papers)

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Research

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16 pages, 6385 KiB

Open AccessArticle

Human Cytomegalovirus Nuclear Egress Complex Subunit, UL53, Associates with Capsids and Myosin Va, but Is Not Important for Capsid Localization towards the Nuclear Periphery

by Adrian R. Wilkie, Mayuri Sharma, Margaret Coughlin, Jean M. Pesola, Maria Ericsson, Jessica L. Lawler, Rosio Fernandez and Donald M. Coen

Viruses 2022, 14(3), 479; https://0-doi-org.brum.beds.ac.uk/10.3390/v14030479 - 26 Feb 2022

Cited by 6 | Viewed by 1677

Abstract

After herpesviruses encapsidate their genomes in replication compartments (RCs) within the nuclear interior, capsids migrate to the inner nuclear membrane (INM) for nuclear egress. For human cytomegalovirus (HCMV), capsid migration depends at least in part on nuclear myosin Va. It has been reported for certain herpesviruses that the nucleoplasmic subunit of the viral nuclear egress complex (NEC) is important for this migration. To address whether this is true for HCMV, we used mass spectrometry and multiple other methods to investigate associations among the HCMV NEC nucleoplasmic subunit, UL53, myosin Va, major capsid protein, and/or capsids. We also generated complementing cells to derive and test HCMV mutants null for UL53 or the INM NEC subunit, UL50, for their importance for these associations and, using electron microscopy, for intranuclear distribution of capsids. We found modest associations among the proteins tested, which were enhanced in the absence of UL50. However, we found no role for UL53 in the interactions of myosin Va with capsids or the percentage of capsids outside RC-like inclusions in the nucleus. Thus, UL53 associates somewhat with myosin Va and capsids, but, contrary to reports regarding its homologs in other herpesviruses, is not important for migration of capsids towards the INM. Full article

(This article belongs to the Special Issue Viruses and Nuclear Egress)

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13 pages, 3458 KiB

Open AccessArticle

Tegument Protein pp150 Sequence-Specific Peptide Blocks Cytomegalovirus Infection

by Dipanwita Mitra, Mohammad H. Hasan, John T. Bates, Gene L. Bidwell III and Ritesh Tandon

Viruses 2021, 13(11), 2277; https://0-doi-org.brum.beds.ac.uk/10.3390/v13112277 - 15 Nov 2021

Cited by 1 | Viewed by 3243

Abstract

Human cytomegalovirus (HCMV) tegument protein pp150 is essential for the completion of the final steps in virion maturation. Earlier studies indicated that three pp150nt (N-terminal one-third of pp150) conformers cluster on each triplex (Tri1, Tri2A and Tri2B), and extend towards small capsid proteins atop nearby major capsid proteins, forming a net-like layer of tegument densities that enmesh and stabilize HCMV capsids. Based on this atomic detail, we designed several peptides targeting pp150nt. Our data show significant reduction in virus growth upon treatment with one of these peptides (pep-CR2) with an IC₅₀ of 1.33 μM and no significant impact on cell viability. Based on 3D modeling, pep-CR2 specifically interferes with the pp150–capsid binding interface. Cells pre-treated with pep-CR2 and infected with HCMV sequester pp150 in the nucleus, indicating a mechanistic disruption of pp150 loading onto capsids and subsequent nuclear egress. Furthermore, pep-CR2 effectively inhibits mouse cytomegalovirus (MCMV) infection in cell culture, paving the way for future animal testing. Combined, these results indicate that CR2 of pp150 is amenable to targeting by a peptide inhibitor, and can be developed into an effective antiviral. Full article

(This article belongs to the Special Issue Viruses and Nuclear Egress)

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16 pages, 3114 KiB

Open AccessArticle

The HSV1 Tail-Anchored Membrane Protein pUL34 Contains a Basic Motif That Supports Active Transport to the Inner Nuclear Membrane Prior to Formation of the Nuclear Egress Complex

by Christina Funk, Débora Marques da Silveira e Santos, Melanie Ott, Verena Raschbichler and Susanne M. Bailer

Viruses 2021, 13(8), 1544; https://0-doi-org.brum.beds.ac.uk/10.3390/v13081544 - 05 Aug 2021

Cited by 2 | Viewed by 1798

Abstract

Herpes simplex virus type 1 nucleocapsids are released from the host nucleus by a budding process through the nuclear envelope called nuclear egress. Two viral proteins, the integral membrane proteins pUL34 and pUL31, form the nuclear egress complex at the inner nuclear membrane, which is critical for this process. The nuclear import of both proteins ensues separately from each other: pUL31 is actively imported through the central pore channel, while pUL34 is transported along the peripheral pore membrane. With this study, we identified a functional bipartite NLS between residues 178 and 194 of pUL34. pUL34 lacking its NLS is mislocalized to the TGN but retargeted to the ER upon insertion of the authentic NLS or a mimic NLS, independent of the insertion site. If co-expressed with pUL31, either of the pUL34-NLS variants is efficiently, although not completely, targeted to the nuclear rim where co-localization with pUL31 and membrane budding seem to occur, comparable to the wild-type. The viral mutant HSV1(17⁺)Lox-UL34-NLS mt is modestly attenuated but viable and associated with localization of pUL34-NLS mt to both the nuclear periphery and cytoplasm. We propose that targeting of pUL34 to the INM is facilitated by, but not dependent on, the presence of an NLS, thereby supporting NEC formation and viral replication. Full article

(This article belongs to the Special Issue Viruses and Nuclear Egress)

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15 pages, 16511 KiB

Open AccessArticle

Role of Vesicle-Associated Membrane Protein-Associated Proteins (VAP) A and VAPB in Nuclear Egress of the Alphaherpesvirus Pseudorabies Virus

by Anna D. Dorsch, Julia E. Hölper, Kati Franzke, Luca M. Zaeck, Thomas C. Mettenleiter and Barbara G. Klupp

Viruses 2021, 13(6), 1117; https://0-doi-org.brum.beds.ac.uk/10.3390/v13061117 - 10 Jun 2021

Cited by 2 | Viewed by 2945

Abstract

The molecular mechanism affecting translocation of newly synthesized herpesvirus nucleocapsids from the nucleus into the cytoplasm is still not fully understood. The viral nuclear egress complex (NEC) mediates budding at and scission from the inner nuclear membrane, but the NEC is not sufficient for efficient fusion of the primary virion envelope with the outer nuclear membrane. Since no other viral protein was found to be essential for this process, it was suggested that a cellular machinery is recruited by viral proteins. However, knowledge on fusion mechanisms involving the nuclear membranes is rare. Recently, vesicle-associated membrane protein-associated protein B (VAPB) was shown to play a role in nuclear egress of herpes simplex virus 1 (HSV-1). To test this for the related alphaherpesvirus pseudorabies virus (PrV), we mutated genes encoding VAPB and VAPA by CRISPR/Cas9-based genome editing in our standard rabbit kidney cells (RK13), either individually or in combination. Single as well as double knockout cells were tested for virus propagation and for defects in nuclear egress. However, no deficiency in virus replication nor any effect on nuclear egress was obvious suggesting that VAPB and VAPA do not play a significant role in this process during PrV infection in RK13 cells. Full article

(This article belongs to the Special Issue Viruses and Nuclear Egress)

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21 pages, 7297 KiB

Open AccessArticle

Phenotypical Characterization of the Nuclear Egress of Recombinant Cytomegaloviruses Reveals Defective Replication upon ORF-UL50 Deletion but Not pUL50 Phosphosite Mutation

by Sigrun Häge, Eric Sonntag, Adriana Svrlanska, Eva Maria Borst, Anne-Charlotte Stilp, Deborah Horsch, Regina Müller, Barbara Kropff, Jens Milbradt, Thomas Stamminger, Ursula Schlötzer-Schrehardt and Manfred Marschall

Viruses 2021, 13(2), 165; https://0-doi-org.brum.beds.ac.uk/10.3390/v13020165 - 22 Jan 2021

Cited by 11 | Viewed by 1972

Abstract

Nuclear egress is a common herpesviral process regulating nucleocytoplasmic capsid release. For human cytomegalovirus (HCMV), the nuclear egress complex (NEC) is determined by the pUL50-pUL53 core that regulates multicomponent assembly with NEC-associated proteins and capsids. Recently, NEC crystal structures were resolved for α-, β- and γ-herpesviruses, revealing profound structural conservation, which was not mirrored, however, by primary sequence and binding properties. The NEC binding principle is based on hook-into-groove interaction through an N-terminal hook-like pUL53 protrusion that embraces an α-helical pUL50 binding groove. So far, pUL50 has been considered as the major kinase-interacting determinant and massive phosphorylation of pUL50-pUL53 was assigned to NEC formation and functionality. Here, we addressed the question of phenotypical changes of ORF-UL50-mutated HCMVs. Surprisingly, our analyses did not detect a predominant replication defect for most of these viral mutants, concerning parameters of replication kinetics (qPCR), viral protein production (Western blot/CoIP) and capsid egress (confocal imaging/EM). Specifically, only the ORF-UL50 deletion rescue virus showed a block of genome synthesis during late stages of infection, whereas all phosphosite mutants exhibited marginal differences compared to wild-type or revertants. These results (i) emphasize a rate-limiting function of pUL50 for nuclear egress, and (ii) demonstrate that mutations in all mapped pUL50 phosphosites may be largely compensated. A refined mechanistic concept points to a multifaceted nuclear egress regulation, for which the dependence on the expression and phosphorylation of pUL50 is discussed. Full article

(This article belongs to the Special Issue Viruses and Nuclear Egress)

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Review

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21 pages, 1846 KiB

Open AccessReview

Human Cytomegalovirus Egress: Overcoming Barriers and Co-Opting Cellular Functions

by Veronica Sanchez and William Britt

Viruses 2022, 14(1), 15; https://0-doi-org.brum.beds.ac.uk/10.3390/v14010015 - 22 Dec 2021

Cited by 12 | Viewed by 3300

Abstract

The assembly of human cytomegalovirus (HCMV) and other herpesviruses includes both nuclear and cytoplasmic phases. During the prolonged replication cycle of HCMV, the cell undergoes remarkable changes in cellular architecture that include marked increases in nuclear size and structure as well as the reorganization of membranes in cytoplasm. Similarly, significant changes occur in cellular metabolism, protein trafficking, and cellular homeostatic functions. These cellular modifications are considered integral in the efficient assembly of infectious progeny in productively infected cells. Nuclear egress of HCMV nucleocapsids is thought to follow a pathway similar to that proposed for other members of the herpesvirus family. During this process, viral nucleocapsids must overcome structural barriers in the nucleus that limit transit and, ultimately, their delivery to the cytoplasm for final assembly of progeny virions. HCMV, similar to other herpesviruses, encodes viral functions that co-opt cellular functions to overcome these barriers and to bridge the bilaminar nuclear membrane. In this brief review, we will highlight some of the mechanisms that define our current understanding of HCMV egress, relying heavily on the current understanding of egress of the more well-studied α-herpesviruses, HSV-1 and PRV. Full article

(This article belongs to the Special Issue Viruses and Nuclear Egress)

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15 pages, 2205 KiB

Open AccessReview

Herpesvirus Nuclear Egress across the Outer Nuclear Membrane

by Richard J. Roller and David C. Johnson

Viruses 2021, 13(12), 2356; https://0-doi-org.brum.beds.ac.uk/10.3390/v13122356 - 24 Nov 2021

Cited by 6 | Viewed by 2442

Abstract

Herpesvirus capsids are assembled in the nucleus and undergo a two-step process to cross the nuclear envelope. Capsids bud into the inner nuclear membrane (INM) aided by the nuclear egress complex (NEC) proteins UL31/34. At that stage of egress, enveloped virions are found for a short time in the perinuclear space. In the second step of nuclear egress, perinuclear enveloped virions (PEVs) fuse with the outer nuclear membrane (ONM) delivering capsids into the cytoplasm. Once in the cytoplasm, capsids undergo re-envelopment in the Golgi/trans-Golgi apparatus producing mature virions. This second step of nuclear egress is known as de-envelopment and is the focus of this review. Compared with herpesvirus envelopment at the INM, much less is known about de-envelopment. We propose a model in which de-envelopment involves two phases: (i) fusion of the PEV membrane with the ONM and (ii) expansion of the fusion pore leading to release of the viral capsid into the cytoplasm. The first phase of de-envelopment, membrane fusion, involves four herpes simplex virus (HSV) proteins: gB, gH/gL, gK and UL20. gB is the viral fusion protein and appears to act to perturb membranes and promote fusion. gH/gL may also have similar properties and appears to be able to act in de-envelopment without gB. gK and UL20 negatively regulate these fusion proteins. In the second phase of de-envelopment (pore expansion and capsid release), an alpha-herpesvirus protein kinase, US3, acts to phosphorylate NEC proteins, which normally produce membrane curvature during envelopment. Phosphorylation of NEC proteins reverses tight membrane curvature, causing expansion of the membrane fusion pore and promoting release of capsids into the cytoplasm. Full article

(This article belongs to the Special Issue Viruses and Nuclear Egress)

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13 pages, 2220 KiB

Open AccessReview

When in Need of an ESCRT: The Nature of Virus Assembly Sites Suggests Mechanistic Parallels between Nuclear Virus Egress and Retroviral Budding

by Kevin M. Rose, Stephanie J. Spada, Vanessa M. Hirsch and Fadila Bouamr

Viruses 2021, 13(6), 1138; https://0-doi-org.brum.beds.ac.uk/10.3390/v13061138 - 13 Jun 2021

Cited by 12 | Viewed by 4177

Abstract

The proper assembly and dissemination of progeny virions is a fundamental step in virus replication. As a whole, viruses have evolved a myriad of strategies to exploit cellular compartments and mechanisms to ensure a successful round of infection. For enveloped viruses such as retroviruses and herpesviruses, acquisition and incorporation of cellular membrane is an essential process during the formation of infectious viral particles. To do this, these viruses have evolved to hijack the host Endosomal Sorting Complexes Required for Transport (ESCRT-I, -II, and -III) to coordinate the sculpting of cellular membrane at virus assembly and dissemination sites, in seemingly different, yet fundamentally similar ways. For instance, at the plasma membrane, ESCRT-I recruitment is essential for HIV-1 assembly and budding, while it is dispensable for the release of HSV-1. Further, HSV-1 was shown to recruit ESCRT-III for nuclear particle assembly and egress, a process not used by retroviruses during replication. Although the cooption of ESCRTs occurs in two separate subcellular compartments and at two distinct steps for these viral lifecycles, the role fulfilled by ESCRTs at these sites appears to be conserved. This review discusses recent findings that shed some light on the potential parallels between retroviral budding and nuclear egress and proposes a model where HSV-1 nuclear egress may occur through an ESCRT-dependent mechanism. Full article

(This article belongs to the Special Issue Viruses and Nuclear Egress)

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17 pages, 2038 KiB

Open AccessReview

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

by Jun Arii

Viruses 2021, 13(5), 754; https://0-doi-org.brum.beds.ac.uk/10.3390/v13050754 - 25 Apr 2021

Cited by 20 | Viewed by 3700

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. Full article

(This article belongs to the Special Issue Viruses and Nuclear Egress)

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20 pages, 2996 KiB

Open AccessReview

Conquering the Nuclear Envelope Barriers by EBV Lytic Replication

by Chung-Pei Lee and Mei-Ru Chen

Viruses 2021, 13(4), 702; https://0-doi-org.brum.beds.ac.uk/10.3390/v13040702 - 18 Apr 2021

Cited by 13 | Viewed by 3617 | Correction

Abstract

The nuclear envelope (NE) of eukaryotic cells has a highly structural architecture, comprising double lipid-bilayer membranes, nuclear pore complexes, and an underlying nuclear lamina network. The NE structure is held in place through the membrane-bound LINC (linker of nucleoskeleton and cytoskeleton) complex, spanning the inner and outer nuclear membranes. The NE functions as a barrier between the nucleus and cytoplasm and as a transverse scaffold for various cellular processes. Epstein–Barr virus (EBV) is a human pathogen that infects most of the world’s population and is associated with several well-known malignancies. Within the nucleus, the replicated viral DNA is packaged into capsids, which subsequently egress from the nucleus into the cytoplasm for tegumentation and final envelopment. There is increasing evidence that viral lytic gene expression or replication contributes to the pathogenesis of EBV. Various EBV lytic proteins regulate and modulate the nuclear envelope structure in different ways, especially the viral BGLF4 kinase and the nuclear egress complex BFRF1/BFRF2. From the aspects of nuclear membrane structure, viral components, and fundamental nucleocytoplasmic transport controls, this review summarizes our findings and recently updated information on NE structure modification and NE-related cellular processes mediated by EBV. Full article

(This article belongs to the Special Issue Viruses and Nuclear Egress)

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