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Identification and characterization of a new E3 ubiquitin ligase in white spot syndrome virus involved in virus latency.

ABSTRACT: White spot syndrome virus (WSSV) is one major pathogen in shrimp aquaculture. WSSV ORF403 is predicted to encode a protein of 641 amino acids, which contains a C3H2C2 RING structure. In the presence of an E2 conjugating enzyme from shrimp, WSSV403 can ubiquitinate itself in vitro, indicating it can function as a viral E3 ligase. Besides, WSSV403 E3 ligase can be activated by a series of E2 variants. Based on RT-PCR and Real time PCR, we detected transcription of WSSV403 in the commercial specific-pathogen-free (SPF) shrimp, suggesting its role as a latency-associated gene. Identified in yeast two-hybrid screening and verified by pull-down assays, WSSV403 is able to bind to a shrimp protein phosphatase (PPs), which was characterized before as an interaction partner for another latent protein WSSV427. Our studies suggest that WSSV403 is a regulator of latency state of WSSV by virtue of its E3 ligase function.

SUBMITTER: He F

PROVIDER: S-EPMC2614973 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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Identification and characterization of a new E3 ubiquitin ligase in white spot syndrome virus involved in virus latency.

He Fang F Kwang Jimmy J

Virology journal 20081217

White spot syndrome virus (WSSV) is one major pathogen in shrimp aquaculture. WSSV ORF403 is predicted to encode a protein of 641 amino acids, which contains a C3H2C2 RING structure. In the presence of an E2 conjugating enzyme from shrimp, WSSV403 can ubiquitinate itself in vitro, indicating it can function as a viral E3 ligase. Besides, WSSV403 E3 ligase can be activated by a series of E2 variants. Based on RT-PCR and Real time PCR, we detected transcription of WSSV403 in the commercial specifi ...[more]

PMID: 19087357

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Project description:UnlabelledViruses have evolved mechanisms to hijack components of cellular E3 ubiquitin ligases, thus modulating the ubiquitination pathway. However, the biological relevance of such mechanisms for viral pathogenesis in vivo remains largely unknown. Here, we utilized murid herpesvirus 4 (MuHV-4) infection of mice as a model system to address the role of MuHV-4 latency-associated nuclear antigen (mLANA) E3 ligase activity in gammaherpesvirus latent infection. We show that specific mutations in the mLANA SOCS box (V199A, V199A/L202A, or P203A/P206A) disrupted mLANA's ability to recruit Elongin C and Cullin 5, thereby impairing the formation of the Elongin BC/Cullin 5/SOCS (EC5S(mLANA)) complex and mLANA's E3 ligase activity on host NF-κB and Myc. Although these mutations resulted in considerably reduced mLANA binding to viral terminal repeat DNA as assessed by electrophoretic mobility shift assay (EMSA), the mutations did not disrupt mLANA's ability to mediate episome persistence. In vivo, MuHV-4 recombinant viruses bearing these mLANA SOCS box mutations exhibited a deficit in latency amplification in germinal center (GC) B cells. These findings demonstrate that the E3 ligase activity of mLANA contributes to gammaherpesvirus-driven GC B cell proliferation. Hence, pharmacological inhibition of viral E3 ligase activity through targeting SOCS box motifs is a putative strategy to control gammaherpesvirus-driven lymphoproliferation and associated disease.ImportanceThe gammaherpesviruses Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) cause lifelong persistent infection and play causative roles in several human malignancies. Colonization of B cells is crucial for virus persistence, and access to the B cell compartment is gained by virus-driven proliferation in germinal center (GC) B cells. Infection of B cells is predominantly latent, with the viral genome persisting as a multicopy episome and expressing only a small subset of viral genes. Here, we focused on latency-associated nuclear antigen (mLANA) encoded by murid herpesvirus-4 (MuHV-4), which exhibits homology in sequence, structure, and function to KSHV LANA (kLANA), thereby allowing the study of LANA-mediated pathogenesis in mice. Our experiments show that mLANA's E3 ubiquitin ligase activity is necessary for efficient expansion of latency in GC B cells, suggesting that the development of pharmacological inhibitors of LANA E3 ubiquitin ligase activity may allow strategies to interfere with gammaherpesvirus-driven lymphoproliferation and associated disease.

Dataset Information

Identification and characterization of a new E3 ubiquitin ligase in white spot syndrome virus involved in virus latency.

Publications

Identification and characterization of a new E3 ubiquitin ligase in white spot syndrome virus involved in virus latency.

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