Kaposi's sarcoma herpesvirus latency-associated nuclear antigen broadly regulates viral gene expression and is essential for lytic infection.
Kaposi's sarcoma herpesvirus (KSHV) is a leading cause of malignancy in AIDS and current therapies are limited. Like all herpesviruses, KSHV infection can be latent or lytic. KSHV latency-associated nuclear antigen (LANA) is essential for viral genome persistence during latent infection. LANA a...
Saved in:
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2024-01-01
|
| Series: | PLoS Pathogens |
| Online Access: | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1011907&type=printable |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849704942377369600 |
|---|---|
| author | Shijun Li Mengbo Wang Nicholas Van Sciver Agnieszka Szymula Vinayak Sadasivam Tumuluri Athira George Akshaya Ramachandran Komal Raina Catarina N Costa Bo Zhao Majid Kazemian J Pedro Simas Kenneth M Kaye |
| author_facet | Shijun Li Mengbo Wang Nicholas Van Sciver Agnieszka Szymula Vinayak Sadasivam Tumuluri Athira George Akshaya Ramachandran Komal Raina Catarina N Costa Bo Zhao Majid Kazemian J Pedro Simas Kenneth M Kaye |
| author_sort | Shijun Li |
| collection | DOAJ |
| description | Kaposi's sarcoma herpesvirus (KSHV) is a leading cause of malignancy in AIDS and current therapies are limited. Like all herpesviruses, KSHV infection can be latent or lytic. KSHV latency-associated nuclear antigen (LANA) is essential for viral genome persistence during latent infection. LANA also maintains latency by antagonizing expression and function of the KSHV lytic switch protein, RTA. Here, we find LANA null KSHV is not capable of lytic replication, indicating a requirement for LANA. While LANA promoted both lytic and latent gene expression in cells partially permissive for lytic infection, it repressed expression in non-permissive cells. Importantly, forced RTA expression in non-permissive cells led to induction of lytic infection and LANA switched to promote, rather than repress, most lytic viral gene expression. When basal viral gene expression levels were high, LANA promoted expression, but repressed expression at low basal levels unless RTA expression was forcibly induced. LANA's effects were broad, but virus gene specific, extending to an engineered, recombinant viral GFP under control of host EF1α promoter, but not to host EF1α. Together, these results demonstrate that, in addition to its essential role in genome maintenance, LANA broadly regulates viral gene expression, and is required for high levels of lytic gene expression during lytic infection. Strategies that target LANA are expected to abolish KSHV infection. |
| format | Article |
| id | doaj-art-b33daf9f0dca4183849c72279d8b02b9 |
| institution | DOAJ |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2024-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-b33daf9f0dca4183849c72279d8b02b92025-08-20T03:16:35ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742024-01-01201e101190710.1371/journal.ppat.1011907Kaposi's sarcoma herpesvirus latency-associated nuclear antigen broadly regulates viral gene expression and is essential for lytic infection.Shijun LiMengbo WangNicholas Van SciverAgnieszka SzymulaVinayak Sadasivam TumuluriAthira GeorgeAkshaya RamachandranKomal RainaCatarina N CostaBo ZhaoMajid KazemianJ Pedro SimasKenneth M KayeKaposi's sarcoma herpesvirus (KSHV) is a leading cause of malignancy in AIDS and current therapies are limited. Like all herpesviruses, KSHV infection can be latent or lytic. KSHV latency-associated nuclear antigen (LANA) is essential for viral genome persistence during latent infection. LANA also maintains latency by antagonizing expression and function of the KSHV lytic switch protein, RTA. Here, we find LANA null KSHV is not capable of lytic replication, indicating a requirement for LANA. While LANA promoted both lytic and latent gene expression in cells partially permissive for lytic infection, it repressed expression in non-permissive cells. Importantly, forced RTA expression in non-permissive cells led to induction of lytic infection and LANA switched to promote, rather than repress, most lytic viral gene expression. When basal viral gene expression levels were high, LANA promoted expression, but repressed expression at low basal levels unless RTA expression was forcibly induced. LANA's effects were broad, but virus gene specific, extending to an engineered, recombinant viral GFP under control of host EF1α promoter, but not to host EF1α. Together, these results demonstrate that, in addition to its essential role in genome maintenance, LANA broadly regulates viral gene expression, and is required for high levels of lytic gene expression during lytic infection. Strategies that target LANA are expected to abolish KSHV infection.https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1011907&type=printable |
| spellingShingle | Shijun Li Mengbo Wang Nicholas Van Sciver Agnieszka Szymula Vinayak Sadasivam Tumuluri Athira George Akshaya Ramachandran Komal Raina Catarina N Costa Bo Zhao Majid Kazemian J Pedro Simas Kenneth M Kaye Kaposi's sarcoma herpesvirus latency-associated nuclear antigen broadly regulates viral gene expression and is essential for lytic infection. PLoS Pathogens |
| title | Kaposi's sarcoma herpesvirus latency-associated nuclear antigen broadly regulates viral gene expression and is essential for lytic infection. |
| title_full | Kaposi's sarcoma herpesvirus latency-associated nuclear antigen broadly regulates viral gene expression and is essential for lytic infection. |
| title_fullStr | Kaposi's sarcoma herpesvirus latency-associated nuclear antigen broadly regulates viral gene expression and is essential for lytic infection. |
| title_full_unstemmed | Kaposi's sarcoma herpesvirus latency-associated nuclear antigen broadly regulates viral gene expression and is essential for lytic infection. |
| title_short | Kaposi's sarcoma herpesvirus latency-associated nuclear antigen broadly regulates viral gene expression and is essential for lytic infection. |
| title_sort | kaposi s sarcoma herpesvirus latency associated nuclear antigen broadly regulates viral gene expression and is essential for lytic infection |
| url | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1011907&type=printable |
| work_keys_str_mv | AT shijunli kaposissarcomaherpesviruslatencyassociatednuclearantigenbroadlyregulatesviralgeneexpressionandisessentialforlyticinfection AT mengbowang kaposissarcomaherpesviruslatencyassociatednuclearantigenbroadlyregulatesviralgeneexpressionandisessentialforlyticinfection AT nicholasvansciver kaposissarcomaherpesviruslatencyassociatednuclearantigenbroadlyregulatesviralgeneexpressionandisessentialforlyticinfection AT agnieszkaszymula kaposissarcomaherpesviruslatencyassociatednuclearantigenbroadlyregulatesviralgeneexpressionandisessentialforlyticinfection AT vinayaksadasivamtumuluri kaposissarcomaherpesviruslatencyassociatednuclearantigenbroadlyregulatesviralgeneexpressionandisessentialforlyticinfection AT athirageorge kaposissarcomaherpesviruslatencyassociatednuclearantigenbroadlyregulatesviralgeneexpressionandisessentialforlyticinfection AT akshayaramachandran kaposissarcomaherpesviruslatencyassociatednuclearantigenbroadlyregulatesviralgeneexpressionandisessentialforlyticinfection AT komalraina kaposissarcomaherpesviruslatencyassociatednuclearantigenbroadlyregulatesviralgeneexpressionandisessentialforlyticinfection AT catarinancosta kaposissarcomaherpesviruslatencyassociatednuclearantigenbroadlyregulatesviralgeneexpressionandisessentialforlyticinfection AT bozhao kaposissarcomaherpesviruslatencyassociatednuclearantigenbroadlyregulatesviralgeneexpressionandisessentialforlyticinfection AT majidkazemian kaposissarcomaherpesviruslatencyassociatednuclearantigenbroadlyregulatesviralgeneexpressionandisessentialforlyticinfection AT jpedrosimas kaposissarcomaherpesviruslatencyassociatednuclearantigenbroadlyregulatesviralgeneexpressionandisessentialforlyticinfection AT kennethmkaye kaposissarcomaherpesviruslatencyassociatednuclearantigenbroadlyregulatesviralgeneexpressionandisessentialforlyticinfection |