Pseudorabies virus US3 leads to filamentous actin disassembly and contributes to viral genome delivery to the nucleus

Jacob, Thary; Broeke, Céline Van den; Grauwet, Korneel; Baert, Kim; Claessen, Christophe; Pelsmaeker, Steffi De; Waesberghe, Cliff Van; Favoreel, Herman

doi:10.1016/j.vetmic.2015.03.023

Cited by 18 publications

(10 citation statements)

References 45 publications

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“…Similar results on the effect of pUS3 on virus replication were previously obtained after deletion of US3 in HSV-1, BHV-1, PRV, and MDV [18,19,20,34]. Similarly, targeting the catalytic active site of EHV-1 pUS3 significantly affected virus replication and cell-to-cell spread as shown before in the case of BHV-5, PRV and HSV-2 [33,35,36]. One possible explanation for the stark effect seen is the involvement of the pUS3 protein kinase in the release of primarily enveloped viruses from the nucleus, which leads to the accumulation of virions between the inner and outer nuclear membrane in the absence of the kinase and may consequently result in a less efficient infection of neighboring cells [19].…”

Section: Discussionsupporting

confidence: 80%

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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Section: Discussionsupporting

confidence: 80%

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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“…Cell fractionation. Cell fractionation was done as described before (93). Briefly, cell pellets were resuspended in ice-cold lysis buffer (as described above) and incubated at 4°C for 20 min with gentle shaking.…”

Section: Methodsmentioning

confidence: 99%

Pseudorabies Virus Infection of Epithelial Cells Leads to Persistent but Aberrant Activation of the NF-κB Pathway, Inhibiting Hallmark NF-κB-Induced Proinflammatory Gene Expression

Romero

Waesberghe

Favoreel

2020

J Virol

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The nuclear factor kappa B (NF-κB) is a potent transcription factor, activation of which typically results in robust proinflammatory signaling and triggering of fast negative feedback modulators to avoid excessive inflammatory responses. Here, we report that infection of epithelial cells, including primary porcine respiratory epithelial cells, with the porcine alphaherpesvirus pseudorabies virus (PRV) results in the gradual and persistent activation of NF-κB, illustrated by proteasome-dependent degradation of the inhibitory NF-κB regulator IκB and nuclear translocation and phosphorylation of the NF-κB subunit p65. PRV-induced persistent activation of NF-κB does not result in expression of negative feedback loop genes, like the gene for IκBα or A20, and does not trigger expression of prototypical proinflammatory genes, like the gene for tumor necrosis factor alpha (TNF-α) or interleukin-6 (IL-6). In addition, PRV infection inhibits TNF-α-induced canonical NF-κB activation. Hence, PRV infection triggers persistent NF-κB activation in an unorthodox way and dramatically modulates the NF-κB signaling axis, preventing typical proinflammatory gene expression and the responsiveness of cells to canonical NF-κB signaling, which may aid the virus in modulating early proinflammatory responses in the infected host. IMPORTANCE The NF-κB transcription factor is activated via different key inflammatory pathways and typically results in the fast expression of several proinflammatory genes as well as negative feedback loop genes to prevent excessive inflammation. In the current report, we describe that infection of cells with the porcine alphaherpesvirus pseudorabies virus (PRV) triggers a gradual and persistent aberrant activation of NF-κB, which does not result in expression of hallmark proinflammatory or negative feedback loop genes. In addition, although PRV-induced NF-κB activation shares some mechanistic features with canonical NF-κB activation, it also shows remarkable differences; e.g., it is largely independent of the canonical IκB kinase (IKK) and even renders infected cells resistant to canonical NF-κB activation by the inflammatory cytokine TNF-α. Aberrant PRV-induced NF-κB activation may therefore paradoxically serve as a viral immune evasion strategy and may represent an important tool to unravel currently unknown mechanisms and consequences of NF-κB activation.

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“…Upon fusion-based entry at the plasma membrane, the PECC encounters cortical filamentous actin (F-actin) that impedes intracellular capsid trafficking (Jacob et al, 2015;Maurer et al, 2008). As already noted, Akt signaling initiated prior to entry may help dismantle this intrinsic hurdle to infection (Liu and Cohen, 2015;Nicola and Straus, 2004).…”

Section: Navigating the Cellular Landscapementioning

confidence: 99%

“…Cofilin activation is driven by the pUS3 component of the PECC (Jacob et al, 2013). In the absence of pUS3, genome delivery to the nucleus is less efficient, but can be restored by depolymerizing F-actin with cytochalasin D (Jacob et al, 2015). Thus, pUS3 is directly involved in breeching the cortical actin and allowing the capsid to gain deeper access to the cytoplasm (Figure 3).…”

Section: Navigating the Cellular Landscapementioning

confidence: 99%

Navigating the Cytoplasm: Delivery of the Alphaherpesvirus Genome to the Nucleus

Smith¹

2021

Current Issues in Molecular Biology

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Herpesviruses virions are large and complex structures that deliver their genetic content to nuclei upon entering cells. This property is not unusual as many other viruses including the adenoviruses, orthomyxoviruses, papillomaviruses, polyomaviruses, and retroviruses, do likewise. However, the means by which viruses in the alphaherpesvirinae subfamily accomplish this fundamental stage of the infectious cycle is tied to their defining ability to efficiently invade the nervous system. Fusion of the viral envelope with a cell membrane results in the deposition of the capsid, along with an assortment of tegument proteins, into the cytosol. Establishment of infection requires that the capsid traverse the cytosol, dock at a nuclear pore, and inject its genome into the nucleoplasm. Accumulating evidence indicates that the capsid is not the effector of this delivery process, but is instead shepherded by tegument proteins that remain capsid bound. At the same time, tegument proteins that are released from the capsid upon entry act to increase the susceptibility of the cell to the ensuing infection. Mucosal epithelial cells and neurons are both susceptible to alphaherpesvirus infection and, together, provide the niche to caister.com/cimb 171 Curr. Issues Mol. Biol. Vol. 41Navigating the Cytoplasm Smith which these viruses have adapted. Although much has been revealed about the functions of de novo expressed tegument proteins during the late stages of assembly and egress, this review will specifically address the roles of tegument proteins brought into the cell with the incoming virion, and our current understanding of alphaherpesvirus genome delivery to nuclei.

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Pseudorabies virus US3 leads to filamentous actin disassembly and contributes to viral genome delivery to the nucleus

Cited by 18 publications

References 45 publications

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

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

Pseudorabies Virus Infection of Epithelial Cells Leads to Persistent but Aberrant Activation of the NF-κB Pathway, Inhibiting Hallmark NF-κB-Induced Proinflammatory Gene Expression

Navigating the Cytoplasm: Delivery of the Alphaherpesvirus Genome to the Nucleus

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