Pereira, Anna; Gama Gomes Leite, FlaviaIST Austria; Brasil, Bruno; Soares Martins, Jamaria; Torres, Alice; Pimenta, Paulo; Souto Padrón, Thais; Tranktman, Paula; Ferreira, Paulo; Kroon, Erna; Bonjardim, Cláudio
Viral manipulation of transduction pathways associated with key cellular functions such as survival, response to microbial infection, and cytoskeleton reorganization can provide the supportive milieu for a productive infection. Here, we demonstrate that vaccinia virus (VACV) infection leads to activation of the stress-activated protein kinase (SAPK)/extracellular signal-regulated kinase (ERK) 4/7 (MKK4/7)-c-Jun N-terminal protein kinase 1/2 (JNK1/2) pathway; further, the stimulation of this pathway requires postpenetration, prereplicative events in the viral replication cycle. Although the formation of intracellular mature virus (IMV) was not affected in MKK4/7- or JNK1/2-knockout (KO) cells, we did note an accentuated deregulation of microtubule and actin network organization in infected JNK1/2-KO cells. This was followed by deregulated viral trafficking to the periphery and enhanced enveloped particle release. Furthermore, VACV infection induced alterations in the cell contractility and morphology, and cell migration was reduced in the JNK-KO cells. In addition, phosphorylation of proteins implicated with early cell contractility and cell migration, such as microtubule-associated protein 1B and paxillin, respectively, was not detected in the VACV-infected KO cells. In sum, our findings uncover a regulatory role played by the MKK4/7-JNK1/2 pathway in cytoskeleton reorganization during VACV infection.
Journal of Virology
This work was supported by grants from Fundação de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG), the Brazilian Federal Agency for Support and Evaluation of Graduate Education (CAPES), and the National Council for Scientific and Technological Development (CNPq). A.C.T.C.P., B.S.A.F.B., F.G.G.L., and J.A.P.S.-M. were recipients of predoctoral fellowships from CNPq. C.A.B., E.G.K., T.S.-P., P.F.P.P., and P.C.P.F. are recipients of research fellowships from CNPq. We are grateful to Angela S. Lopes, Ilda M. V. Gama, João R. dos Santos, and Andreza A. Carvalho for their secretarial/technical assistance and to Fernanda Gambogi for help with immunofluorescence microscopy. We also thank M. C. Sogayar (Department of Biochemistry, University of São Paulo, São Paulo, Brazil), who kindly provided us with the A31 cell line, and R. Davis (Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, MA) for the WT and JNK1/2-, MKK4-, MKK7-, and MKK4/7-KO cells. VACV WR was from C. Jungwirth (Universität Würzburg, Würzburg, Germany). The recombinant VACV vF13L-GFP and the rabbit polyclonal antibodies against viral proteins, B5R, D8L, L1R, and A36R, were from B. Moss (NIAID, Bethesda, MD). The pcDNA3-Myc-JNK2-MKK7 WT plasmid was from Eugen Kerkhoff (Universität Würzburg, Würzburg, Germany). We also thank Flávio G. da Fonseca (UFMG, Belo Horizonte, MG, Brazil) and Kathleen A. Boyle (Medical College of Wisconsin, Milwaukee, WI) for critically reading the manuscript.
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Pereira A, Leite F, Brasil B, et al. A vaccinia virus-driven interplay between the MKK4/7-JNK1/2 pathway and cytoskeleton reorganization. Journal of Virology. 2012;86(1):172-184. doi:10.1128/JVI.05638-11
Pereira, A., Leite, F., Brasil, B., Soares Martins, J., Torres, A., Pimenta, P., … Bonjardim, C. (2012). A vaccinia virus-driven interplay between the MKK4/7-JNK1/2 pathway and cytoskeleton reorganization. Journal of Virology, 86(1), 172–184. https://doi.org/10.1128/JVI.05638-11
Pereira, Anna, Flávia Leite, Bruno Brasil, Jamaria Soares Martins, Alice Torres, Paulo Pimenta, Thais Souto Padrón, et al. “A Vaccinia Virus-Driven Interplay between the MKK4/7-JNK1/2 Pathway and Cytoskeleton Reorganization.” Journal of Virology 86, no. 1 (2012): 172–84. https://doi.org/10.1128/JVI.05638-11.
A. Pereira et al., “A vaccinia virus-driven interplay between the MKK4/7-JNK1/2 pathway and cytoskeleton reorganization,” Journal of Virology, vol. 86, no. 1, pp. 172–184, 2012.
Pereira A, Leite F, Brasil B, Soares Martins J, Torres A, Pimenta P, Souto Padrón T, Tranktman P, Ferreira P, Kroon E, Bonjardim C. 2012. A vaccinia virus-driven interplay between the MKK4/7-JNK1/2 pathway and cytoskeleton reorganization. Journal of Virology. 86(1), 172–184.
Pereira, Anna, et al. “A Vaccinia Virus-Driven Interplay between the MKK4/7-JNK1/2 Pathway and Cytoskeleton Reorganization.” Journal of Virology, vol. 86, no. 1, ASM, 2012, pp. 172–84, doi:10.1128/JVI.05638-11.
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