Alphaherpesviruses and the Cytoskeleton in Neuronal Infections

Zaichick, Sofia; Bohannon, Kevin P.; Smith, Greg

doi:10.3390/v3070941

Cited by 35 publications

(33 citation statements)

References 313 publications

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“…Both the actin and microtubule cytoskeleton have well-established roles during herpesvirus infection [21,133,134]. Actin filaments (F-actin) play an essential role in short-distance cargo movement [135,136,137,138].…”

Section: Utilization Of the Host Cytoskeleton For Directional Sprementioning

confidence: 99%

“…Alphaherpesvirus infections induce alterations of actin filaments, microtubules and other cellular organelles in a variety of cell types [21,133,134]. For example, the viral kinase, Us3, promotes disassembly of actin stress fibers and outgrowth of cellular protrusions that are proposed to enhance cell-to-cell spread and viral egress [216].…”

Section: Utilization Of the Host Cytoskeleton For Directional Sprementioning

confidence: 99%

“…Very little is currently known about viral particle dynamics in dendrites. The vast majority of studies have focused on sorting and transport of herpesvirus particles in axons during entry and egress [11,20,21]. …”

Section: Introductionmentioning

confidence: 99%

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Directional Spread of Alphaherpesviruses in the Nervous System

Kramer

Enquist

2013

Viruses

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Alphaherpesviruses are pathogens that invade the nervous systems of their mammalian hosts. Directional spread of infection in the nervous system is a key component of the viral lifecycle and is critical for the onset of alphaherpesvirus-related diseases. Many alphaherpesvirus infections originate at peripheral sites, such as epithelial tissues, and then enter neurons of the peripheral nervous system (PNS), where lifelong latency is established. Following reactivation from latency and assembly of new viral particles, the infection typically spreads back out towards the periphery. These spread events result in the characteristic lesions (cold sores) commonly associated with herpes simplex virus (HSV) and herpes zoster (shingles) associated with varicella zoster virus (VZV). Occasionally, the infection spreads transsynaptically from the PNS into higher order neurons of the central nervous system (CNS). Spread of infection into the CNS, while rarer in natural hosts, often results in severe consequences, including death. In this review, we discuss the viral and cellular mechanisms that govern directional spread of infection in the nervous system. We focus on the molecular events that mediate long distance directional transport of viral particles in neurons during entry and egress.

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Section: Utilization Of the Host Cytoskeleton For Directional Sprementioning

confidence: 99%

Section: Utilization Of the Host Cytoskeleton For Directional Sprementioning

confidence: 99%

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Directional Spread of Alphaherpesviruses in the Nervous System

Kramer

Enquist

2013

Viruses

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“…During infection, several alphaherpesviruses, including herpes simplex virus type 1 and type 2 (HSV-1 and HSV-2), varicella zoster virus (VZV), pseudorabies virus (PRV), bovine herpesvirus type 1 (BHV-1), and Marek’s disease virus (MDV) modulate the actin cytoskeleton at almost every step of virus replication, from entry to egress and direct cell-to-cell spread. These events are dependent mostly on the kinase activity of pUS3 [6,8,9,10]. For PRV, group A p21-activated kinases (PAKs) were found to be involved in the pUS3-induced modulation of the actin cytoskeleton and the migration of virus particles through cell projections, ultimately leading to infection of neighboring cells [11].…”

Section: Introductionmentioning

confidence: 99%

The Role of the Equine Herpesvirus Type 1 (EHV-1) US3-Encoded Protein Kinase in Actin Reorganization and Nuclear Egress

Proft

Spiesschaert

Izume

et al. 2016

Viruses

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The serine-threonine protein kinase encoded by US3 gene (pUS3) of alphaherpesviruses was shown to modulate actin reorganization, cell-to-cell spread, and virus egress in a number of virus species. However, the role of the US3 orthologues of equine herpesvirus type 1 and 4 (EHV-1 and EHV-4) has not yet been studied. Here, we show that US3 is not essential for virus replication in vitro. However, growth rates and plaque diameters of a US3-deleted EHV-1 and a mutant in which the catalytic active site was destroyed were significantly reduced when compared with parental and revertant viruses or a virus in which EHV-1 US3 was replaced with the corresponding EHV-4 gene. The reduced plaque sizes were consistent with accumulation of primarily enveloped virions in the perinuclear space of the US3-negative EHV-1, a phenotype that was also rescued by the EHV-4 orthologue. Furthermore, actin stress fiber disassembly was significantly more pronounced in cells infected with parental EHV-1, revertant, or the recombinant EHV-1 expressing EHV-4 US3. Finally, we observed that deletion of US3 in EHV-1 did not affect the expression of adhesion molecules on the surface of infected cells.

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“…Although the tegument compartment of herpesvirus is pleomorphic and has no distinguishable substructures, it is roughly divided into outer tegument and inner tegument layers (5,6). Upon cell entry, the outer tegument proteins are released into the host cell cytoplasm where some of them perform functions needed early in the infection process, while the inner tegument proteins remain associated with the nucleocapsid and participate in its transport to the nucleus via the microtubule/dynein motor system (7)(8)(9)(10)(11)(12).…”

mentioning

confidence: 99%

Organization of Capsid-Associated Tegument Components in Kaposi's Sarcoma-Associated Herpesvirus

Dai

Gong

et al. 2014

J Virol

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Capsid-associated tegument proteins have been identified in alpha-and betaherpesviruses to play an essential role in viral DNA packaging. Whether and how such tegument proteins exist in gammaherpesviruses have been mysteries. Here, we report a 6-Å-resolution cryo-electron microscopy (cryo-EM) structure of Kaposi's sarcoma-associated herpesvirus (KSHV) virion, a member of the oncogenic gammaherpesvirus subfamily. The KSHV virion structure reveals, for the first time, how capsid-associated tegument proteins are organized in a gammaherpesvirus, with five tegument densities capping each penton vertex, a pattern highly similar to that in alphaherpesvirus but completely different from that in betaherpesvirus. Each KSHV tegument density can be divided into three prominent regions: a penton-binding globular region, a helix-bundle stalk region, and a ␤-sheet-rich triplexbinding region. Fitting of the crystal structure of the truncated HSV-1 UL25 protein (the KSHV ORF19 homolog) and secondary structure analysis of the full-length ORF19 established that ORF19 constitutes the globular region with an N-terminal, 60-amino-acid-long helix extending into the stalk region. Matching secondary structural features resolved in the cryo-EM density with secondary structures predicted by sequence analysis identifies the triplex-binding region to be ORF32, a homolog of alphaherpesvirus UL17. Despite the high level of tegument structural similarities between KSHV and alphaherpesvirus, an ORF19 monomer in KSHV, in contrast to a UL25 dimer in alphaherpesviruses, binds each penton subunit, an observation that correlates with conformational differences in their pentons. This newly discovered organization of triplex-ORF32-ORF19 also resolves a longstanding mystery surrounding the virion location and conformation of alphaherpesvirus UL25 protein. IMPORTANCESeveral capsid-associated tegument proteins have been identified in the alpha-and betaherpesvirus subfamilies of the Herpesviridae. These tegument proteins play essential roles in viral propagation and are potential drug targets for curbing herpesvirus infections. However, no such tegument proteins have been identified for gammaherpesviruses, the third herpesvirus subfamily, which contains members causing several human cancers. Here, by high-resolution cryo-EM, we show the three-dimensional structure of the capsid-associated tegument proteins in the prototypical member of gammaherpesviruses, KSHV. The cryo-EM structure reveals that the organization of KSHV capsid-associated tegument proteins is highly similar to that in alphaherpesvirus but completely different from that in betaherpesvirus. Structural analyses further localize ORF19 and ORF32 proteins (the alphaherpesvirus UL25 and UL17 homologs in KSHV, respectively) in the KSHV capsid-associated tegument cryo-EM structure. These findings also resolve a long-standing mystery regarding the location and conformation of alphaherpesvirus UL25 protein inside the virion.

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Alphaherpesviruses and the Cytoskeleton in Neuronal Infections

Cited by 35 publications

References 313 publications

Directional Spread of Alphaherpesviruses in the Nervous System

Directional Spread of Alphaherpesviruses in the Nervous System

The Role of the Equine Herpesvirus Type 1 (EHV-1) US3-Encoded Protein Kinase in Actin Reorganization and Nuclear Egress

Organization of Capsid-Associated Tegument Components in Kaposi's Sarcoma-Associated Herpesvirus

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