Nuclear Egress of Herpesviruses

Hellberg, Teresa; Paßvogel, Lars; Schulz, Katja; Klupp, Barbara G.; Mettenleiter, Thomas C.

doi:10.1016/bs.aivir.2015.10.002

Cited by 55 publications

(27 citation statements)

References 329 publications

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“…S4), but it did not exceed ~10% of the level that is present in a typical tegument (Text S2). Thus, while it appears that a few inner tegument proteins are acquired in the nucleus (reviewed in references 31 and 32), our results imply that the majority of tegument protein is acquired after the egressing nucleocapsid enters the cytoplasm.…”

Section: Discussionmentioning

confidence: 57%

The Primary Enveloped Virion of Herpes Simplex Virus 1: Its Role in Nuclear Egress

Newcomb

Fontana

Winkler

et al. 2017

mBio

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Many viruses migrate between different cellular compartments for successive stages of assembly. The HSV-1 capsid assembles in the nucleus and then transfers into the cytoplasm. First, the capsid buds through the inner nuclear membrane, becoming coated with nuclear egress complex (NEC) protein. This yields a primary enveloped virion (PEV) whose envelope fuses with the outer nuclear membrane, releasing the capsid into the cytoplasm. We investigated the associated molecular mechanisms by isolating PEVs from US3-null-infected cells and imaging them by cryo-electron microscopy and tomography. (pUS3 is a viral protein kinase in whose absence PEVs accumulate in the perinuclear space.) Unlike mature extracellular virions, PEVs have very few glycoprotein spikes. PEVs are ~20% smaller than mature virions, and the little space available between the capsid and the NEC layer suggests that most tegument proteins are acquired later in the egress pathway. Previous studies have proposed that NEC is organized as hexamers in honeycomb arrays in PEVs, but we find arrays of heptameric rings in extracts from US3-null-infected cells. In a PEV, NEC contacts the capsid predominantly via the pUL17/pUL25 complexes which are located close to the capsid vertices. Finally, the NEC layer dissociates from the capsid as it leaves the nucleus, possibly in response to pUS3-mediated phosphorylation. Overall, nuclear egress emerges as a process driven by a program of multiple weak interactions.

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Section: Discussionmentioning

confidence: 57%

The Primary Enveloped Virion of Herpes Simplex Virus 1: Its Role in Nuclear Egress

Newcomb

Fontana

Winkler

et al. 2017

mBio

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“…Recent analysis revealed amazing features of core NEC proteins of α-, βand γ-herpesviruses, including sequence-specific, structural and functional properties. Functional details of NEC assembly and the regulatory role of NECs in nuclear egress appear closely related and almost congruent between herpesviruses in several aspects, such as recruiting effector proteins responsible for nuclear lamina rearrangement ( Figure 1) [2,27]. Similarly, many structural properties of NEC proteins were also found conserved and qualitatively mostly consistent [28,29].…”

Section: Sequence Conservation Of Herpesviral Core Nuclear Egress Commentioning

confidence: 80%

Patterns of Autologous and Nonautologous Interactions between Core Nuclear Egress Complex (NEC) Proteins of α-, β- and γ-Herpesviruses

Häge

Sonntag

Borst

et al. 2020

Viruses

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Nuclear egress is a regulated process shared by α-, β- and γ-herpesviruses. The core nuclear egress complex (NEC) is composed of the membrane-anchored protein homologs of human cytomegalovirus (HCMV) pUL50, murine cytomegalovirus (MCMV) pM50, Epstein–Barr virus (EBV) BFRF1 or varicella zoster virus (VZV) Orf24, which interact with the autologous NEC partners pUL53, pM53, BFLF2 or Orf27, respectively. Their recruitment of additional proteins leads to the assembly of a multicomponent NEC, coordinately regulating viral nucleocytoplasmic capsid egress. Here, the functionality of VZV, HCMV, MCMV and EBV core NECs was investigated by coimmunoprecipitation and confocal imaging analyses. Furthermore, a recombinant MCMV, harboring a replacement of ORF M50 by UL50, was analyzed both in vitro and in vivo. In essence, core NEC interactions were strictly limited to autologous NEC pairs and only included one measurable nonautologous interaction between the homologs of HCMV and MCMV. A comparative analysis of MCMV-WT versus MCMV-UL50-infected murine fibroblasts revealed almost identical phenotypes on the levels of protein and genomic replication kinetics. In infected BALB/c mice, virus spread to lung and other organs was found comparable between these viruses, thus stating functional complementarity. In conclusion, our study underlines that herpesviral core NEC proteins are functionally conserved regarding complementarity of core NEC interactions, which were found either virus-specific or restricted within subfamilies.

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“…For primary envelopment, nucleocapsids need to bypass the nuclear lamina to engage the INM, which is then deformed to wrap around the nucleocapsid. Vesiculation is finalized by the abscission of the INM (2,3,6). HSV-1 NEC and/or its homolog(s) in other herpesvirus(es) was reported to have multiple roles in these steps during primary envelopment, including the recruitment of nucleocapsids to the INM, deformation of the INM, and recruitment of host cellular factors, such as members of the protein kinase C (PKC) family and components of the ESCRT-III machinery, which are thought to dissolve the nuclear lamina by the phosphorylation of lamin proteins (7) and to mediate abscission of the INM (8), respectively (6,9,10).…”

mentioning

confidence: 99%

Roles of the Interhexamer Contact Site for Hexagonal Lattice Formation of the Herpes Simplex Virus 1 Nuclear Egress Complex in Viral Primary Envelopment and Replication

Arii

Takeshima

Maruzuru

et al. 2019

J Virol

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During the nuclear export of nascent nucleocapsids of herpes simplex virus 1 (HSV-1), the nucleocapsids acquire a primary envelope by budding through the inner nuclear membrane into the perinuclear space between the inner and outer nuclear membranes. This unique budding process, termed primary envelopment, is initiated by the nuclear egress complex (NEC), composed of the HSV-1 UL31 and UL34 proteins. Earlier biochemical approaches have shown that the NEC has an intrinsic ability to vesiculate membranes through the formation of a hexagonal lattice structure. The significance of intrahexamer interactions of the NEC in the primary envelopment of HSV-1-infected cells has been reported. In contrast, the contribution of lattice formation of the NEC hexamer to primary envelopment in HSV-1-infected cells remains to be elucidated. Therefore, we constructed and characterized a recombinant HSV-1 strain carrying an amino acid substitution in a UL31 residue that is an interhexamer contact site for the lattice formation of the NEC hexamer. This mutation was reported to destabilize the interhexamer interactions of the HSV-1 NEC. Here, we demonstrate that the mutation causes the aberrant accumulation of nucleocapsids in the nucleus and reduces viral replication in Vero and HeLa cells. Thus, the ability of HSV-1 to form the hexagonal lattice structure of the NEC was linked to an increase in primary envelopment and viral replication. Our results suggest that the lattice formation of the NEC hexamer has an important role in HSV-1 replication by regulating primary envelopment. IMPORTANCE The scaffolding proteins of several envelope viruses required for virion assembly form high-order lattice structures. However, information on the significance of their lattice formation in infected cells is limited. Herpesviruses acquire envelopes twice during their viral replication. The first envelop acquisition (primary envelopment) is one of the steps in the vesicle-mediated nucleocytoplasmic transport of nascent nucleocapsids, which is unique in biology. HSV-1 NEC, thought to be conserved in all members of the Herpesviridae family, is critical for primary envelopment and was shown to form a hexagonal lattice structure. Here, we investigated the significance of the interhexamer contact site for hexagonal lattice formation of the NEC in HSV-1-infected cells and present evidence suggesting that the lattice formation of the NEC hexamer has an important role in HSV-1 replication by regulating primary envelopment. Our results provide insights into the mechanisms of the envelopment of herpesviruses and other envelope viruses.

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Nuclear Egress of Herpesviruses

Cited by 55 publications

References 329 publications

The Primary Enveloped Virion of Herpes Simplex Virus 1: Its Role in Nuclear Egress

The Primary Enveloped Virion of Herpes Simplex Virus 1: Its Role in Nuclear Egress

Patterns of Autologous and Nonautologous Interactions between Core Nuclear Egress Complex (NEC) Proteins of α-, β- and γ-Herpesviruses

Roles of the Interhexamer Contact Site for Hexagonal Lattice Formation of the Herpes Simplex Virus 1 Nuclear Egress Complex in Viral Primary Envelopment and Replication

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