KSHV-encoded LANA protects the cellular replication machinery from hypoxia induced degradation.
Kaposi's sarcoma associated herpesvirus (KSHV), like all herpesviruses maintains lifelong persistence with its host genome in latently infected cells with only a small fraction of cells showing signatures of productive lytic replication. Modulation of cellular signaling pathways by KSHV-encoded...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2019-09-01
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| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1008025 |
| _version_ | 1818734941956997120 |
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| author | Rajnish Kumar Singh Zachary L Lamplugh Fengchao Lang Yan Yuan Paul Lieberman Jianxin You Erle S Robertson |
| author_facet | Rajnish Kumar Singh Zachary L Lamplugh Fengchao Lang Yan Yuan Paul Lieberman Jianxin You Erle S Robertson |
| author_sort | Rajnish Kumar Singh |
| collection | DOAJ |
| description | Kaposi's sarcoma associated herpesvirus (KSHV), like all herpesviruses maintains lifelong persistence with its host genome in latently infected cells with only a small fraction of cells showing signatures of productive lytic replication. Modulation of cellular signaling pathways by KSHV-encoded latent antigens, and microRNAs, as well as some level of spontaneous reactivation are important requirements for establishment of viral-associated diseases. Hypoxia, a prominent characteristic of the microenvironment of cancers, can exert specific effects on cell cycle control, and DNA replication through HIF1α-dependent pathways. Furthermore, hypoxia can induce lytic replication of KSHV. The mechanism by which KSHV-encoded RNAs and antigens regulate cellular and viral replication in the hypoxic microenvironment has yet to be fully elucidated. We investigated replication-associated events in the isogenic background of KSHV positive and negative cells grown under normoxic or hypoxic conditions and discovered an indispensable role of KSHV for sustained cellular and viral replication, through protection of critical components of the replication machinery from degradation at different stages of the process. These include proteins involved in origin recognition, pre-initiation, initiation and elongation of replicating genomes. Our results demonstrate that KSHV-encoded LANA inhibits hypoxia-mediated degradation of these proteins to sustain continued replication of both host and KSHV DNA. The present study provides a new dimension to our understanding of the role of KSHV in survival and growth of viral infected cells growing under hypoxic conditions and suggests potential new strategies for targeted treatment of KSHV-associated cancer. |
| first_indexed | 2024-12-18T00:13:22Z |
| format | Article |
| id | doaj.art-8396c47177b7425a9c05b554a87d5fd2 |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-12-18T00:13:22Z |
| publishDate | 2019-09-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-8396c47177b7425a9c05b554a87d5fd22022-12-21T21:27:36ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742019-09-01159e100802510.1371/journal.ppat.1008025KSHV-encoded LANA protects the cellular replication machinery from hypoxia induced degradation.Rajnish Kumar SinghZachary L LamplughFengchao LangYan YuanPaul LiebermanJianxin YouErle S RobertsonKaposi's sarcoma associated herpesvirus (KSHV), like all herpesviruses maintains lifelong persistence with its host genome in latently infected cells with only a small fraction of cells showing signatures of productive lytic replication. Modulation of cellular signaling pathways by KSHV-encoded latent antigens, and microRNAs, as well as some level of spontaneous reactivation are important requirements for establishment of viral-associated diseases. Hypoxia, a prominent characteristic of the microenvironment of cancers, can exert specific effects on cell cycle control, and DNA replication through HIF1α-dependent pathways. Furthermore, hypoxia can induce lytic replication of KSHV. The mechanism by which KSHV-encoded RNAs and antigens regulate cellular and viral replication in the hypoxic microenvironment has yet to be fully elucidated. We investigated replication-associated events in the isogenic background of KSHV positive and negative cells grown under normoxic or hypoxic conditions and discovered an indispensable role of KSHV for sustained cellular and viral replication, through protection of critical components of the replication machinery from degradation at different stages of the process. These include proteins involved in origin recognition, pre-initiation, initiation and elongation of replicating genomes. Our results demonstrate that KSHV-encoded LANA inhibits hypoxia-mediated degradation of these proteins to sustain continued replication of both host and KSHV DNA. The present study provides a new dimension to our understanding of the role of KSHV in survival and growth of viral infected cells growing under hypoxic conditions and suggests potential new strategies for targeted treatment of KSHV-associated cancer.https://doi.org/10.1371/journal.ppat.1008025 |
| spellingShingle | Rajnish Kumar Singh Zachary L Lamplugh Fengchao Lang Yan Yuan Paul Lieberman Jianxin You Erle S Robertson KSHV-encoded LANA protects the cellular replication machinery from hypoxia induced degradation. PLoS Pathogens |
| title | KSHV-encoded LANA protects the cellular replication machinery from hypoxia induced degradation. |
| title_full | KSHV-encoded LANA protects the cellular replication machinery from hypoxia induced degradation. |
| title_fullStr | KSHV-encoded LANA protects the cellular replication machinery from hypoxia induced degradation. |
| title_full_unstemmed | KSHV-encoded LANA protects the cellular replication machinery from hypoxia induced degradation. |
| title_short | KSHV-encoded LANA protects the cellular replication machinery from hypoxia induced degradation. |
| title_sort | kshv encoded lana protects the cellular replication machinery from hypoxia induced degradation |
| url | https://doi.org/10.1371/journal.ppat.1008025 |
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