Skip to main content
Erschienen in: Archives of Virology 10/2017

15.06.2017 | Original Article

c-Jun integrates signals from both MEK/ERK and MKK/JNK pathways upon vaccinia virus infection

verfasst von: Flávia G. G. Leite, Alice A. Torres, Leonardo C. De Oliveira, André F. P. Da Cruz, Jamária A. P. Soares-Martins, Anna C. T. C. Pereira, Giliane S. Trindade, Jonatas S. Abrahão, Erna G. Kroon, Paulo C. P. Ferreira, Cláudio A. Bonjardim

Erschienen in: Archives of Virology | Ausgabe 10/2017

Einloggen, um Zugang zu erhalten

Abstract

Usurpation of the host’s signalling pathways is a common strategy employed by viruses to promote their successful replication. Here we show that infection with the orthopoxvirus vaccinia virus (VACV) leads to sustained stimulation of c-Jun activity during the entire infective cycle. This stimulation is temporally regulated through MEK/ERK or MKK/JNK pathways, i.e. during the early/mid phase (1 to 6 hpi) and in the late phase (9 to 24 hpi) of the infective cycle, respectively. As a transcriptional regulator, upon infection with VACV, c-Jun is translocated from the cytoplasm to the nucleus, where it binds to the AP-1 DNA sequence found at the promoter region of its target genes. To investigate the role played by c-Jun during VACV replication cycle, we generated cell lines that stably express a c-Jun-dominant negative (DNc-Jun) mutation. Our data revealed that c-Jun is required during early infection to assist with viral DNA replication, as demonstrated by the decreased amount of viral DNA found in the DNc-Jun cells. We also demonstrated that c-Jun regulates the expression of the early growth response gene (egr-1), a gene previously shown to affect VACV replication mediated by MEK/ERK signalling. VACV-induced stimulation of the MKK/JNK/JUN pathway impacts viral dissemination, as we observed a significant reduction in both viral yield, during late stages of infection, and virus plaque size. Collectively, our data suggest that, by modulating the host’s signalling pathways through a common target such as c-Jun, VACV temporally regulates its infective cycle in order to successfully replicate and subsequently spread.
Literatur
1.
Zurück zum Zitat Moss B (2007) Poxviridae: the viruses and their replication. In: Knipe DM, Howley PM (eds) Fields virology. Lippincott Williams and Wilkins, New York, pp 2905–2945 Moss B (2007) Poxviridae: the viruses and their replication. In: Knipe DM, Howley PM (eds) Fields virology. Lippincott Williams and Wilkins, New York, pp 2905–2945
2.
Zurück zum Zitat Smith GL et al (2013) Vaccinia virus immune evasion: mechanisms, virulence and immunogenicity. J Gen Virol 94(Pt 11):2367–2392CrossRefPubMed Smith GL et al (2013) Vaccinia virus immune evasion: mechanisms, virulence and immunogenicity. J Gen Virol 94(Pt 11):2367–2392CrossRefPubMed
3.
Zurück zum Zitat Brady G, Bowie AG (2014) Innate immune activation of NFkappaB and its antagonism by poxviruses. Cytokine Growth Factor Rev 25(5):611–620CrossRefPubMed Brady G, Bowie AG (2014) Innate immune activation of NFkappaB and its antagonism by poxviruses. Cytokine Growth Factor Rev 25(5):611–620CrossRefPubMed
4.
Zurück zum Zitat Bonjardim CA, Ferreira PC, Kroon EG (2009) Interferons: signaling, antiviral and viral evasion. Immunol Lett 122(1):1–11CrossRefPubMed Bonjardim CA, Ferreira PC, Kroon EG (2009) Interferons: signaling, antiviral and viral evasion. Immunol Lett 122(1):1–11CrossRefPubMed
7.
Zurück zum Zitat Andrade AA et al (2004) The vaccinia virus-stimulated mitogen-activated protein kinase (MAPK) pathway is required for virus multiplication. Biochem J 381(Pt 2):437–446CrossRefPubMedPubMedCentral Andrade AA et al (2004) The vaccinia virus-stimulated mitogen-activated protein kinase (MAPK) pathway is required for virus multiplication. Biochem J 381(Pt 2):437–446CrossRefPubMedPubMedCentral
8.
Zurück zum Zitat de Magalhaes JC et al (2001) A mitogenic signal triggered at an early stage of vaccinia virus infection: implication of MEK/ERK and protein kinase A in virus multiplication. J Biol Chem 276(42):38353–38360CrossRefPubMed de Magalhaes JC et al (2001) A mitogenic signal triggered at an early stage of vaccinia virus infection: implication of MEK/ERK and protein kinase A in virus multiplication. J Biol Chem 276(42):38353–38360CrossRefPubMed
9.
Zurück zum Zitat Silva PN et al (2006) Differential role played by the MEK/ERK/EGR-1 pathway in orthopoxviruses vaccinia and cowpox biology. Biochem J 398(1):83–95CrossRefPubMedPubMedCentral Silva PN et al (2006) Differential role played by the MEK/ERK/EGR-1 pathway in orthopoxviruses vaccinia and cowpox biology. Biochem J 398(1):83–95CrossRefPubMedPubMedCentral
11.
Zurück zum Zitat Yang SH, Sharrocks AD, Whitmarsh AJ (2013) MAP kinase signalling cascades and transcriptional regulation. Gene 513(1):1–13CrossRefPubMed Yang SH, Sharrocks AD, Whitmarsh AJ (2013) MAP kinase signalling cascades and transcriptional regulation. Gene 513(1):1–13CrossRefPubMed
12.
Zurück zum Zitat Zeke A et al (2016) JNK signaling: regulation and functions based on complex protein–protein partnerships. Microbiol Mol Biol Rev 80(3):793–835CrossRefPubMedPubMedCentral Zeke A et al (2016) JNK signaling: regulation and functions based on complex protein–protein partnerships. Microbiol Mol Biol Rev 80(3):793–835CrossRefPubMedPubMedCentral
13.
Zurück zum Zitat Krishna M, Narang H (2008) The complexity of mitogen-activated protein kinases (MAPKs) made simple. Cell Mol Life Sci 65(22):3525–3544CrossRefPubMed Krishna M, Narang H (2008) The complexity of mitogen-activated protein kinases (MAPKs) made simple. Cell Mol Life Sci 65(22):3525–3544CrossRefPubMed
15.
Zurück zum Zitat Marshall CJ (1995) Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell 80(2):179–185CrossRefPubMed Marshall CJ (1995) Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell 80(2):179–185CrossRefPubMed
16.
Zurück zum Zitat Plotnikov A et al (2011) The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation. Biochim Biophys Acta 1813(9):1619–1633CrossRefPubMed Plotnikov A et al (2011) The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation. Biochim Biophys Acta 1813(9):1619–1633CrossRefPubMed
17.
Zurück zum Zitat Hazzalin CA, Mahadevan LC (2002) MAPK-regulated transcription: a continuously variable gene switch? Nat Rev Mol Cell Biol 3(1):30–40CrossRefPubMed Hazzalin CA, Mahadevan LC (2002) MAPK-regulated transcription: a continuously variable gene switch? Nat Rev Mol Cell Biol 3(1):30–40CrossRefPubMed
18.
Zurück zum Zitat Dunn C et al (2002) Molecular mechanism and biological functions of c-Jun N-terminal kinase signalling via the c-Jun transcription factor. Cell Signal 14(7):585–593CrossRefPubMed Dunn C et al (2002) Molecular mechanism and biological functions of c-Jun N-terminal kinase signalling via the c-Jun transcription factor. Cell Signal 14(7):585–593CrossRefPubMed
19.
21.
Zurück zum Zitat Liu X, Cohen JI (2015) Epstein–Barr virus (EBV) tegument protein BGLF2 promotes EBV reactivation through activation of the p38 mitogen-activated protein kinase. J Virol 90(2):1129–1138CrossRefPubMedPubMedCentral Liu X, Cohen JI (2015) Epstein–Barr virus (EBV) tegument protein BGLF2 promotes EBV reactivation through activation of the p38 mitogen-activated protein kinase. J Virol 90(2):1129–1138CrossRefPubMedPubMedCentral
22.
23.
Zurück zum Zitat Pereira AC et al (2012) A vaccinia virus-driven interplay between the MKK4/7-JNK1/2 pathway and cytoskeleton reorganization. J Virol 86(1):172–184CrossRefPubMedPubMedCentral Pereira AC et al (2012) A vaccinia virus-driven interplay between the MKK4/7-JNK1/2 pathway and cytoskeleton reorganization. J Virol 86(1):172–184CrossRefPubMedPubMedCentral
24.
Zurück zum Zitat Tournier C et al (2000) Requirement of JNK for stress-induced activation of the cytochrome c-mediated death pathway. Science 288(5467):870–874CrossRefPubMed Tournier C et al (2000) Requirement of JNK for stress-induced activation of the cytochrome c-mediated death pathway. Science 288(5467):870–874CrossRefPubMed
25.
Zurück zum Zitat Alam J et al (1999) Nrf2, a Cap’n’Collar transcription factor, regulates induction of the heme oxygenase-1 gene. J Biol Chem 274(37):26071–26078CrossRefPubMed Alam J et al (1999) Nrf2, a Cap’n’Collar transcription factor, regulates induction of the heme oxygenase-1 gene. J Biol Chem 274(37):26071–26078CrossRefPubMed
26.
Zurück zum Zitat Husain M, Moss B (2001) Vaccinia virus F13L protein with a conserved phospholipase catalytic motif induces colocalization of the B5R envelope glycoprotein in post-Golgi vesicles. J Virol 75(16):7528–7542CrossRefPubMedPubMedCentral Husain M, Moss B (2001) Vaccinia virus F13L protein with a conserved phospholipase catalytic motif induces colocalization of the B5R envelope glycoprotein in post-Golgi vesicles. J Virol 75(16):7528–7542CrossRefPubMedPubMedCentral
27.
28.
Zurück zum Zitat Sambrook J, Fritsch EF, Maniats T (1989) Molecular cloning: a laboratory manual, 2nd edn. Cold Spring Harbor, Cold Spring Harbor Laboratory Sambrook J, Fritsch EF, Maniats T (1989) Molecular cloning: a laboratory manual, 2nd edn. Cold Spring Harbor, Cold Spring Harbor Laboratory
29.
30.
Zurück zum Zitat Schreck I et al (2011) c-Jun localizes to the nucleus independent of its phosphorylation by and interaction with JNK and vice versa promotes nuclear accumulation of JNK. Biochem Biophys Res Commun 407(4):735–740CrossRefPubMed Schreck I et al (2011) c-Jun localizes to the nucleus independent of its phosphorylation by and interaction with JNK and vice versa promotes nuclear accumulation of JNK. Biochem Biophys Res Commun 407(4):735–740CrossRefPubMed
32.
Zurück zum Zitat Schwachtgen JL, Campbell CJ, Braddock M (2000) Full promoter sequence of human early growth response factor-1 (Egr-1): demonstration of a fifth functional serum response element. DNA Seq 10(6):429–432CrossRefPubMed Schwachtgen JL, Campbell CJ, Braddock M (2000) Full promoter sequence of human early growth response factor-1 (Egr-1): demonstration of a fifth functional serum response element. DNA Seq 10(6):429–432CrossRefPubMed
34.
Zurück zum Zitat Soares JA et al (2009) Activation of the PI3K/Akt pathway early during vaccinia and cowpox virus infections is required for both host survival and viral replication. J Virol 83(13):6883–6899CrossRefPubMedPubMedCentral Soares JA et al (2009) Activation of the PI3K/Akt pathway early during vaccinia and cowpox virus infections is required for both host survival and viral replication. J Virol 83(13):6883–6899CrossRefPubMedPubMedCentral
35.
Zurück zum Zitat Schweneker M et al (2012) The vaccinia virus O1 protein is required for sustained activation of extracellular signal-regulated kinase 1/2 and promotes viral virulence. J Virol 86(4):2323–2336CrossRefPubMedPubMedCentral Schweneker M et al (2012) The vaccinia virus O1 protein is required for sustained activation of extracellular signal-regulated kinase 1/2 and promotes viral virulence. J Virol 86(4):2323–2336CrossRefPubMedPubMedCentral
37.
Zurück zum Zitat Avey D et al (2015) Phosphoproteomic analysis of KSHV-infected cells reveals roles of ORF45-activated RSK during lytic replication. PLoS Pathog 11(7):e1004993CrossRefPubMedPubMedCentral Avey D et al (2015) Phosphoproteomic analysis of KSHV-infected cells reveals roles of ORF45-activated RSK during lytic replication. PLoS Pathog 11(7):e1004993CrossRefPubMedPubMedCentral
38.
Zurück zum Zitat Zhang W et al (2016) ERK/c-Jun recruits Tet1 to induce Zta expression and Epstein–Barr virus reactivation through DNA demethylation. Sci Rep 6:34543CrossRefPubMedPubMedCentral Zhang W et al (2016) ERK/c-Jun recruits Tet1 to induce Zta expression and Epstein–Barr virus reactivation through DNA demethylation. Sci Rep 6:34543CrossRefPubMedPubMedCentral
39.
40.
Zurück zum Zitat Oh J, Broyles SS (2005) Host cell nuclear proteins are recruited to cytoplasmic vaccinia virus replication complexes. J Virol 79(20):12852–12860CrossRefPubMedPubMedCentral Oh J, Broyles SS (2005) Host cell nuclear proteins are recruited to cytoplasmic vaccinia virus replication complexes. J Virol 79(20):12852–12860CrossRefPubMedPubMedCentral
41.
Zurück zum Zitat Eferl R, Wagner EF (2003) AP-1: a double-edged sword in tumorigenesis. Nat Rev Cancer 3(11):859–868CrossRefPubMed Eferl R, Wagner EF (2003) AP-1: a double-edged sword in tumorigenesis. Nat Rev Cancer 3(11):859–868CrossRefPubMed
42.
Zurück zum Zitat Leite F, Way M (2015) The role of signalling and the cytoskeleton during Vaccinia virus egress. Virus Res 209:87–99CrossRefPubMed Leite F, Way M (2015) The role of signalling and the cytoskeleton during Vaccinia virus egress. Virus Res 209:87–99CrossRefPubMed
43.
Zurück zum Zitat Javelaud D et al (2003) Disruption of basal JNK activity differentially affects key fibroblast functions important for wound healing. J Biol Chem 278(27):24624–24628CrossRefPubMed Javelaud D et al (2003) Disruption of basal JNK activity differentially affects key fibroblast functions important for wound healing. J Biol Chem 278(27):24624–24628CrossRefPubMed
44.
Zurück zum Zitat Cowan KJ, Storey KB (2003) Mitogen-activated protein kinases: new signaling pathways functioning in cellular responses to environmental stress. J Exp Biol 206(Pt 7):1107–1115CrossRefPubMed Cowan KJ, Storey KB (2003) Mitogen-activated protein kinases: new signaling pathways functioning in cellular responses to environmental stress. J Exp Biol 206(Pt 7):1107–1115CrossRefPubMed
45.
Zurück zum Zitat Xie J et al (2005) Kaposi’s sarcoma-associated herpesvirus induction of AP-1 and interleukin 6 during primary infection mediated by multiple mitogen-activated protein kinase pathways. J Virol 79(24):15027–15037CrossRefPubMedPubMedCentral Xie J et al (2005) Kaposi’s sarcoma-associated herpesvirus induction of AP-1 and interleukin 6 during primary infection mediated by multiple mitogen-activated protein kinase pathways. J Virol 79(24):15027–15037CrossRefPubMedPubMedCentral
46.
Zurück zum Zitat Benn J et al (1996) Hepatitis B virus HBx protein induces transcription factor AP-1 by activation of extracellular signal-regulated and c-Jun N-terminal mitogen-activated protein kinases. J Virol 70(8):4978–4985PubMedPubMedCentral Benn J et al (1996) Hepatitis B virus HBx protein induces transcription factor AP-1 by activation of extracellular signal-regulated and c-Jun N-terminal mitogen-activated protein kinases. J Virol 70(8):4978–4985PubMedPubMedCentral
47.
Zurück zum Zitat Nijhara R et al (2001) Sustained activation of mitogen-activated protein kinases and activator protein 1 by the hepatitis B virus X protein in mouse hepatocytes in vivo. J Virol 75(21):10348–10358CrossRefPubMedPubMedCentral Nijhara R et al (2001) Sustained activation of mitogen-activated protein kinases and activator protein 1 by the hepatitis B virus X protein in mouse hepatocytes in vivo. J Virol 75(21):10348–10358CrossRefPubMedPubMedCentral
Metadaten
Titel
c-Jun integrates signals from both MEK/ERK and MKK/JNK pathways upon vaccinia virus infection
verfasst von
Flávia G. G. Leite
Alice A. Torres
Leonardo C. De Oliveira
André F. P. Da Cruz
Jamária A. P. Soares-Martins
Anna C. T. C. Pereira
Giliane S. Trindade
Jonatas S. Abrahão
Erna G. Kroon
Paulo C. P. Ferreira
Cláudio A. Bonjardim
Publikationsdatum
15.06.2017
Verlag
Springer Vienna
Erschienen in
Archives of Virology / Ausgabe 10/2017
Print ISSN: 0304-8608
Elektronische ISSN: 1432-8798
DOI
https://doi.org/10.1007/s00705-017-3446-6

Weitere Artikel der Ausgabe 10/2017

Archives of Virology 10/2017 Zur Ausgabe

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.