A cancer-associated Epstein-Barr virus BZLF1 promoter variant enhances lytic infection.
Latent Epstein-Barr virus (EBV) infection contributes to both B-cell and epithelial-cell malignancies. However, whether lytic EBV infection also contributes to tumors is unclear, although the association between malaria infection and Burkitt lymphomas (BLs) may involve excessive lytic EBV replicatio...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2018-07-01
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| Series: | PLoS Pathogens |
| Online Access: | http://europepmc.org/articles/PMC6082571?pdf=render |
| _version_ | 1818294848491356160 |
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| author | Jillian A Bristol Reza Djavadian Emily R Albright Carrie B Coleman Makoto Ohashi Mitchell Hayes James C Romero-Masters Elizabeth A Barlow Paul J Farrell Rosemary Rochford Robert F Kalejta Eric C Johannsen Shannon C Kenney |
| author_facet | Jillian A Bristol Reza Djavadian Emily R Albright Carrie B Coleman Makoto Ohashi Mitchell Hayes James C Romero-Masters Elizabeth A Barlow Paul J Farrell Rosemary Rochford Robert F Kalejta Eric C Johannsen Shannon C Kenney |
| author_sort | Jillian A Bristol |
| collection | DOAJ |
| description | Latent Epstein-Barr virus (EBV) infection contributes to both B-cell and epithelial-cell malignancies. However, whether lytic EBV infection also contributes to tumors is unclear, although the association between malaria infection and Burkitt lymphomas (BLs) may involve excessive lytic EBV replication. A particular variant of the viral promoter (Zp) that controls lytic EBV reactivation is over-represented, relative to its frequency in non-malignant tissue, in EBV-positive nasopharyngeal carcinomas and AIDS-related lymphomas. To date, no functional differences between the prototype Zp (Zp-P) and the cancer-associated variant (Zp-V3) have been identified. Here we show that a single nucleotide difference between the Zp-V3 and Zp-P promoters creates a binding site for the cellular transcription factor, NFATc1, in the Zp-V3 (but not Zp-P) variant, and greatly enhances Zp activity and lytic viral reactivation in response to NFATc1-inducing stimuli such as B-cell receptor activation and ionomycin. Furthermore, we demonstrate that restoring this NFATc1-motif to the Zp-P variant in the context of the intact EBV B95.8 strain genome greatly enhances lytic viral reactivation in response to the NFATc1-activating agent, ionomycin, and this effect is blocked by the NFAT inhibitory agent, cyclosporine, as well as NFATc1 siRNA. We also show that the Zp-V3 variant is over-represented in EBV-positive BLs and gastric cancers, and in EBV-transformed B-cell lines derived from EBV-infected breast milk of Kenyan mothers that had malaria during pregnancy. These results demonstrate that the Zp-V3 enhances EBV lytic reactivation to physiologically-relevant stimuli, and suggest that increased lytic infection may contribute to the increased prevalence of this variant in EBV-associated malignancies. |
| first_indexed | 2024-12-13T03:38:16Z |
| format | Article |
| id | doaj.art-befe6fac9f924c28ac976fee9666b00d |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-12-13T03:38:16Z |
| publishDate | 2018-07-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-befe6fac9f924c28ac976fee9666b00d2022-12-22T00:01:00ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742018-07-01147e100717910.1371/journal.ppat.1007179A cancer-associated Epstein-Barr virus BZLF1 promoter variant enhances lytic infection.Jillian A BristolReza DjavadianEmily R AlbrightCarrie B ColemanMakoto OhashiMitchell HayesJames C Romero-MastersElizabeth A BarlowPaul J FarrellRosemary RochfordRobert F KalejtaEric C JohannsenShannon C KenneyLatent Epstein-Barr virus (EBV) infection contributes to both B-cell and epithelial-cell malignancies. However, whether lytic EBV infection also contributes to tumors is unclear, although the association between malaria infection and Burkitt lymphomas (BLs) may involve excessive lytic EBV replication. A particular variant of the viral promoter (Zp) that controls lytic EBV reactivation is over-represented, relative to its frequency in non-malignant tissue, in EBV-positive nasopharyngeal carcinomas and AIDS-related lymphomas. To date, no functional differences between the prototype Zp (Zp-P) and the cancer-associated variant (Zp-V3) have been identified. Here we show that a single nucleotide difference between the Zp-V3 and Zp-P promoters creates a binding site for the cellular transcription factor, NFATc1, in the Zp-V3 (but not Zp-P) variant, and greatly enhances Zp activity and lytic viral reactivation in response to NFATc1-inducing stimuli such as B-cell receptor activation and ionomycin. Furthermore, we demonstrate that restoring this NFATc1-motif to the Zp-P variant in the context of the intact EBV B95.8 strain genome greatly enhances lytic viral reactivation in response to the NFATc1-activating agent, ionomycin, and this effect is blocked by the NFAT inhibitory agent, cyclosporine, as well as NFATc1 siRNA. We also show that the Zp-V3 variant is over-represented in EBV-positive BLs and gastric cancers, and in EBV-transformed B-cell lines derived from EBV-infected breast milk of Kenyan mothers that had malaria during pregnancy. These results demonstrate that the Zp-V3 enhances EBV lytic reactivation to physiologically-relevant stimuli, and suggest that increased lytic infection may contribute to the increased prevalence of this variant in EBV-associated malignancies.http://europepmc.org/articles/PMC6082571?pdf=render |
| spellingShingle | Jillian A Bristol Reza Djavadian Emily R Albright Carrie B Coleman Makoto Ohashi Mitchell Hayes James C Romero-Masters Elizabeth A Barlow Paul J Farrell Rosemary Rochford Robert F Kalejta Eric C Johannsen Shannon C Kenney A cancer-associated Epstein-Barr virus BZLF1 promoter variant enhances lytic infection. PLoS Pathogens |
| title | A cancer-associated Epstein-Barr virus BZLF1 promoter variant enhances lytic infection. |
| title_full | A cancer-associated Epstein-Barr virus BZLF1 promoter variant enhances lytic infection. |
| title_fullStr | A cancer-associated Epstein-Barr virus BZLF1 promoter variant enhances lytic infection. |
| title_full_unstemmed | A cancer-associated Epstein-Barr virus BZLF1 promoter variant enhances lytic infection. |
| title_short | A cancer-associated Epstein-Barr virus BZLF1 promoter variant enhances lytic infection. |
| title_sort | cancer associated epstein barr virus bzlf1 promoter variant enhances lytic infection |
| url | http://europepmc.org/articles/PMC6082571?pdf=render |
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