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...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
American Society for Microbiology
2018-04-01
|
| Series: | mSphere |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mSphere.00138-18 |
| _version_ | 1819043626148167680 |
|---|---|
| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-21T09:59:46Z |
| format | Article |
| id | doaj.art-4b2d9038ac724a1985ec0121ec65e262 |
| institution | Directory Open Access Journal |
| issn | 2379-5042 |
| language | English |
| last_indexed | 2024-12-21T09:59:46Z |
| publishDate | 2018-04-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mSphere |
| spelling | doaj.art-4b2d9038ac724a1985ec0121ec65e2622022-12-21T19:07:58ZengAmerican Society for MicrobiologymSphere2379-50422018-04-013210.1128/mSphere.00138-18BGLF2 Increases Infectivity of Epstein-Barr Virus by Activating AP-1 upon <italic toggle="yes">De Novo</italic> InfectionNatsuno Konishi0Yohei Narita1Fumiya Hijioka2H. M. Abdullah Al Masud3Yoshitaka Sato4Hiroshi Kimura5Takayuki Murata6Department of Virology, Nagoya University Graduate School of Medicine, Nagoya, JapanDepartment of Virology, Nagoya University Graduate School of Medicine, Nagoya, JapanDepartment of Virology, Nagoya University Graduate School of Medicine, Nagoya, JapanDepartment of Virology, Nagoya University Graduate School of Medicine, Nagoya, JapanDepartment of Virology, Nagoya University Graduate School of Medicine, Nagoya, JapanDepartment of Virology, Nagoya University Graduate School of Medicine, Nagoya, JapanDepartment of Virology, Nagoya University Graduate School of Medicine, Nagoya, JapanABSTRACT 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.https://journals.asm.org/doi/10.1128/mSphere.00138-18AP-1BGLF2BRLF1EBVcell signaling |
| spellingShingle | 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 mSphere AP-1 BGLF2 BRLF1 EBV cell signaling |
| title | 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_short | 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 |
| topic | AP-1 BGLF2 BRLF1 EBV cell signaling |
| url | https://journals.asm.org/doi/10.1128/mSphere.00138-18 |
| work_keys_str_mv | AT natsunokonishi bglf2increasesinfectivityofepsteinbarrvirusbyactivatingap1uponitalictoggleyesdenovoitalicinfection AT yoheinarita bglf2increasesinfectivityofepsteinbarrvirusbyactivatingap1uponitalictoggleyesdenovoitalicinfection AT fumiyahijioka bglf2increasesinfectivityofepsteinbarrvirusbyactivatingap1uponitalictoggleyesdenovoitalicinfection AT hmabdullahalmasud bglf2increasesinfectivityofepsteinbarrvirusbyactivatingap1uponitalictoggleyesdenovoitalicinfection AT yoshitakasato bglf2increasesinfectivityofepsteinbarrvirusbyactivatingap1uponitalictoggleyesdenovoitalicinfection AT hiroshikimura bglf2increasesinfectivityofepsteinbarrvirusbyactivatingap1uponitalictoggleyesdenovoitalicinfection AT takayukimurata bglf2increasesinfectivityofepsteinbarrvirusbyactivatingap1uponitalictoggleyesdenovoitalicinfection |