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Rho-ROCK and Rac-PAK signaling pathways have opposing effects on the cell-to-cell spread of Marek's Disease Virus.

Richerioux, N; Blondeau, C; Wiedemann, A; Rémy, S; Vautherot, JF; Denesvre, C; (2012) Rho-ROCK and Rac-PAK signaling pathways have opposing effects on the cell-to-cell spread of Marek's Disease Virus. PLoS One , 7 (8) , Article e44072. 10.1371/journal.pone.0044072. Green open access

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Abstract

Marek's Disease Virus (MDV) is an avian alpha-herpesvirus that only spreads from cell-to-cell in cell culture. While its cell-to-cell spread has been shown to be dependent on actin filament dynamics, the mechanisms regulating this spread remain largely unknown. Using a recombinant BAC20 virus expressing an EGFPVP22 tegument protein, we found that the actin cytoskeleton arrangements and cell-cell contacts differ in the center and periphery of MDV infection plaques, with cells in the latter areas showing stress fibers and rare cellular projections. Using specific inhibitors and activators, we determined that Rho-ROCK pathway, known to regulate stress fiber formation, and Rac-PAK, known to promote lamellipodia formation and destabilize stress fibers, had strong contrasting effects on MDV cell-to-cell spread in primary chicken embryo skin cells (CESCs). Inhibition of Rho and its ROCKs effectors led to reduced plaque sizes whereas inhibition of Rac or its group I-PAKs effectors had the adverse effect. Importantly, we observed that the shape of MDV plaques is related to the semi-ordered arrangement of the elongated cells, at the monolayer level in the vicinity of the plaques. Inhibition of Rho-ROCK signaling also resulted in a perturbation of the cell arrangement and a rounding of plaques. These opposing effects of Rho and Rac pathways in MDV cell-to-cell spread were validated for two parental MDV recombinant viruses with different ex vivo spread efficiencies. Finally, we demonstrated that Rho/Rac pathways have opposing effects on the accumulation of N-cadherin at cell-cell contact regions between CESCs, and defined these contacts as adherens junctions. Considering the importance of adherens junctions in HSV-1 cell-to-cell spread in some cell types, this result makes of adherens junctions maintenance one potential and attractive hypothesis to explain the Rho/Rac effects on MDV cell-to-cell spread. Our study provides the first evidence that MDV cell-to-cell spread is regulated by Rho/Rac signaling.

Type: Article
Title: Rho-ROCK and Rac-PAK signaling pathways have opposing effects on the cell-to-cell spread of Marek's Disease Virus.
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pone.0044072
Publisher version: http://dx.doi.org/10.1371/journal.pone.0044072
Language: English
Additional information: © Richerioux et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Nicolas Richerioux is a PhD student supported by an INRA/(National Institute for Agricultural Research) Région Centre fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Keywords: Actin Cytoskeleton, Adherens Junctions, Animals, Cadherins, Cell Communication, Cellular Microenvironment, Chick Embryo, Herpesvirus 2, Gallid, Lipopolysaccharides, Lysophospholipids, Marek Disease, Movement, Polymerization, Signal Transduction, Skin, Sphingosine, Stress Fibers, p21-Activated Kinases, rac GTP-Binding Proteins, rho GTP-Binding Proteins, rho-Associated Kinases
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
URI: https://discovery.ucl.ac.uk/id/eprint/1385336
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