BGLF2 Increases Infectivity of Epstein-Barr Virus by Activating AP-1 upon <italic toggle="yes">De Novo</italic> Infection

ABSTRACT Epstein-Barr virus (EBV) is a human gammaherpesvirus that causes infectious mononucleosis and several malignancies, such as endemic Burkitt lymphoma and nasopharyngeal carcinoma. Herpesviruses carry genes that can modify cell functions, including transcription and ubiquitination, thereby fa...

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Autores principales:	Natsuno Konishi, Yohei Narita, Fumiya Hijioka, H. M. Abdullah Al Masud, Yoshitaka Sato, Hiroshi Kimura, Takayuki Murata
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	AP-1 BGLF2 BRLF1 EBV cell signaling Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/4b2d9038ac724a1985ec0121ec65e262
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spelling	oai:doaj.org-article:4b2d9038ac724a1985ec0121ec65e2622021-11-15T15:22:14ZBGLF2 Increases Infectivity of Epstein-Barr Virus by Activating AP-1 upon <italic toggle="yes">De Novo</italic> Infection10.1128/mSphere.00138-182379-5042https://doaj.org/article/4b2d9038ac724a1985ec0121ec65e2622018-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00138-18https://doaj.org/toc/2379-5042ABSTRACT Epstein-Barr virus (EBV) is a human gammaherpesvirus that causes infectious mononucleosis and several malignancies, such as endemic Burkitt lymphoma and nasopharyngeal carcinoma. Herpesviruses carry genes that can modify cell functions, including transcription and ubiquitination, thereby facilitating viral growth and survival in infected cells. Using a reporter screening system, we revealed the involvement of several EBV gene products in such processes. Of these, BGLF2 activated the AP-1 signaling pathway through phosphorylation of p38 and c-Jun N-terminal kinase (JNK). Knockout of the BGLF2 gene did not affect viral gene expression and viral genome DNA replication, but resulted in marked reduction of progeny titer. We also found that the BGLF2 disruption resulted in significant loss of infectivity upon de novo infection. Interestingly, expression of a binding partner, BKRF4, repressed the activation of AP-1 by BGLF2. These results shed light on the physiological role of the tegument protein BGLF2. IMPORTANCE Epstein-Barr virus (EBV), an oncogenic gammaherpesvirus, carries ~80 genes. While several genes have been investigated extensively, most lytic genes remain largely unexplored. Therefore, we cloned 71 EBV lytic genes into an expression vector and used reporter assays to screen for factors that activate signal transduction pathways, viral and cellular promoters. BGLF2 activated the AP-1 signaling pathway, likely by interacting with p38 and c-Jun N-terminal kinase (JNK), and increased infectivity of the virus. We also revealed that BKRF4 can negatively regulate AP-1 activity. Therefore, it is suggested that EBV exploits and modifies the AP-1 signaling pathway for its replication and survival.Natsuno KonishiYohei NaritaFumiya HijiokaH. M. Abdullah Al MasudYoshitaka SatoHiroshi KimuraTakayuki MurataAmerican Society for MicrobiologyarticleAP-1BGLF2BRLF1EBVcell signalingMicrobiologyQR1-502ENmSphere, Vol 3, Iss 2 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	AP-1 BGLF2 BRLF1 EBV cell signaling Microbiology QR1-502
spellingShingle	AP-1 BGLF2 BRLF1 EBV cell signaling Microbiology QR1-502 Natsuno Konishi Yohei Narita Fumiya Hijioka H. M. Abdullah Al Masud Yoshitaka Sato Hiroshi Kimura Takayuki Murata BGLF2 Increases Infectivity of Epstein-Barr Virus by Activating AP-1 upon <italic toggle="yes">De Novo</italic> Infection
description	ABSTRACT Epstein-Barr virus (EBV) is a human gammaherpesvirus that causes infectious mononucleosis and several malignancies, such as endemic Burkitt lymphoma and nasopharyngeal carcinoma. Herpesviruses carry genes that can modify cell functions, including transcription and ubiquitination, thereby facilitating viral growth and survival in infected cells. Using a reporter screening system, we revealed the involvement of several EBV gene products in such processes. Of these, BGLF2 activated the AP-1 signaling pathway through phosphorylation of p38 and c-Jun N-terminal kinase (JNK). Knockout of the BGLF2 gene did not affect viral gene expression and viral genome DNA replication, but resulted in marked reduction of progeny titer. We also found that the BGLF2 disruption resulted in significant loss of infectivity upon de novo infection. Interestingly, expression of a binding partner, BKRF4, repressed the activation of AP-1 by BGLF2. These results shed light on the physiological role of the tegument protein BGLF2. IMPORTANCE Epstein-Barr virus (EBV), an oncogenic gammaherpesvirus, carries ~80 genes. While several genes have been investigated extensively, most lytic genes remain largely unexplored. Therefore, we cloned 71 EBV lytic genes into an expression vector and used reporter assays to screen for factors that activate signal transduction pathways, viral and cellular promoters. BGLF2 activated the AP-1 signaling pathway, likely by interacting with p38 and c-Jun N-terminal kinase (JNK), and increased infectivity of the virus. We also revealed that BKRF4 can negatively regulate AP-1 activity. Therefore, it is suggested that EBV exploits and modifies the AP-1 signaling pathway for its replication and survival.
format	article
author	Natsuno Konishi Yohei Narita Fumiya Hijioka H. M. Abdullah Al Masud Yoshitaka Sato Hiroshi Kimura Takayuki Murata
author_facet	Natsuno Konishi Yohei Narita Fumiya Hijioka H. M. Abdullah Al Masud Yoshitaka Sato Hiroshi Kimura Takayuki Murata
author_sort	Natsuno Konishi
title	BGLF2 Increases Infectivity of Epstein-Barr Virus by Activating AP-1 upon <italic toggle="yes">De Novo</italic> Infection
title_short	BGLF2 Increases Infectivity of Epstein-Barr Virus by Activating AP-1 upon <italic toggle="yes">De Novo</italic> Infection
title_full	BGLF2 Increases Infectivity of Epstein-Barr Virus by Activating AP-1 upon <italic toggle="yes">De Novo</italic> Infection
title_fullStr	BGLF2 Increases Infectivity of Epstein-Barr Virus by Activating AP-1 upon <italic toggle="yes">De Novo</italic> Infection
title_full_unstemmed	BGLF2 Increases Infectivity of Epstein-Barr Virus by Activating AP-1 upon <italic toggle="yes">De Novo</italic> Infection
title_sort	bglf2 increases infectivity of epstein-barr virus by activating ap-1 upon <italic toggle="yes">de novo</italic> infection
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/4b2d9038ac724a1985ec0121ec65e262
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BGLF2 Increases Infectivity of Epstein-Barr Virus by Activating AP-1 upon <italic toggle="yes">De Novo</italic> Infection

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