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NEDDylation Is Essential for Kaposi’s Sarcoma-Associated Herpesvirus Latency and Lytic Reactivation and Represents a Novel Anti-KSHV Target

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Kaposi’s sarcoma-associated herpesvirus (KSHV) causes Kaposi’s sarcoma (KS) and primary effusion lymphoma (PEL), often fatal malignancies afflicting HIV-infected patients. Previous research has shown that blockade of the ubiquitin proteasome system (UPS, a normal quality control pathway that degrades cellular proteins) is able to kill KSHV-infected lymphoma cells. A large component of the UPS is made up by the protein family known as the cullin-RING ubiquitin ligases (CRLs), which are activated by NEDD8 (a process known as NEDDylation). Recently, an inhibitor of NEDDylation (MLN4924) was developed and is currently in clinical trials as an anti-cancer drug. As NEDDylation has not been investigated for many viruses, we used this to compound examine its importance in KSHV biology. Firstly we show that NEDDylation is essential for the viability of KSHV-infected lymphoma cells, and MLN4924 treatment killed these cells by blocking NF-κB activity (required for KSHV latency gene expression and KSHV-associated cancer). Furthermore, we show that NEDDylation is required for KSHV to replicate its genome, a critical step in the production of new virus particles. Therefore, this research has identified a novel molecular mechanism that governs KSHV replication. Furthermore, it demonstrates that NEDDylation is a viable target for the treatment of KSHV-associated malignancies.

Vyšlo v časopise: NEDDylation Is Essential for Kaposi’s Sarcoma-Associated Herpesvirus Latency and Lytic Reactivation and Represents a Novel Anti-KSHV Target. PLoS Pathog 11(3): e32767. doi:10.1371/journal.ppat.1004771
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004771

Souhrn

Kaposi’s sarcoma-associated herpesvirus (KSHV) causes Kaposi’s sarcoma (KS) and primary effusion lymphoma (PEL), often fatal malignancies afflicting HIV-infected patients. Previous research has shown that blockade of the ubiquitin proteasome system (UPS, a normal quality control pathway that degrades cellular proteins) is able to kill KSHV-infected lymphoma cells. A large component of the UPS is made up by the protein family known as the cullin-RING ubiquitin ligases (CRLs), which are activated by NEDD8 (a process known as NEDDylation). Recently, an inhibitor of NEDDylation (MLN4924) was developed and is currently in clinical trials as an anti-cancer drug. As NEDDylation has not been investigated for many viruses, we used this to compound examine its importance in KSHV biology. Firstly we show that NEDDylation is essential for the viability of KSHV-infected lymphoma cells, and MLN4924 treatment killed these cells by blocking NF-κB activity (required for KSHV latency gene expression and KSHV-associated cancer). Furthermore, we show that NEDDylation is required for KSHV to replicate its genome, a critical step in the production of new virus particles. Therefore, this research has identified a novel molecular mechanism that governs KSHV replication. Furthermore, it demonstrates that NEDDylation is a viable target for the treatment of KSHV-associated malignancies.

Zdroje

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