Identification of Properties of the Kaposi's Sarcoma-Associated Herpesvirus Latent Origin of Replication That Are Essential for the Efficient Establishment and Maintenance of Intact Plasmids

Shrestha, Prabha; Sugden, Bill

doi:10.1128/jvi.00742-14

Cited by 12 publications

(21 citation statements)

References 63 publications

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“…The related gammaherpesvirus KSHV differs profoundly from EBV. Detailed examinations have shown that the KSHV genome encodes 16 or more sets of replication origins, each located within a copy of its terminal repeats (TRs) and uses one viral protein, LANA1, to bind these origins and mediate their DNA synthesis ( Ballestas et al, 1999 ; Cotter and Robertson, 1999 ; Ballestas and Kaye, 2001 ; Hu et al, 2002 ; Krithivas et al, 2002 ; Barbera et al, 2004 ; Ye et al, 2004 ; Shrestha and Sugden, 2014 ). LANA1 binds these replication origins directly but does not tether them directly to chromosomal DNA.…”

Section: Introductionmentioning

confidence: 99%

Kaposi’s sarcoma–associated herpesvirus stably clusters its genomes across generations to maintain itself extrachromosomally

Chiu

Sugden

Fox

et al. 2017

Journal of Cell Biology

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Several human tumor viruses, including Kaposi’s sarcoma–associated herpesvirus (KSHV), maintain their plasmid genomes by tethering them to cellular chromosomes. Chiu et al. identify a viral segregation mechanism: KSHV stably clusters some of its genomes, which are inherited as units. Clustering, as predicted computationally and observed in live cells, rapidly establishes high viral copy numbers in cells.

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Section: Introductionmentioning

confidence: 99%

Kaposi’s sarcoma–associated herpesvirus stably clusters its genomes across generations to maintain itself extrachromosomally

Chiu

Sugden

Fox

et al. 2017

Journal of Cell Biology

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“…LANA is dispensable for lytic replication (17)(18)(19). The two essential functions of either protein are to support latent genome replication and to partition the viral plasmid during mitosis to maintain the same genome copy number per cell (20)(21)(22)(23)(24)(25)(26). PELs are dependent on KSHV for survival (27,28).…”

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confidence: 99%

Epstein–Barr virus enhances genome maintenance of Kaposi sarcoma-associated herpesvirus

Bigi

Landis

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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Primary effusion lymphoma (PEL) is a B cell lymphoma that is always associated with Kaposi's sarcoma-associated herpesvirus (KSHV) and in many cases also with Epstein-Barr virus (EBV); however, the requirement for EBV coinfection is not clear. Here, we demonstrate that adding exogenous EBV to KSHV + single-positive PEL leads to increased KSHV genome maintenance and KSHV latency-associated nuclear antigen (LANA) expression. To show that EBV was necessary for naturally coinfected PEL, we nucleofected KSHV + /EBV + PEL cell lines with an EBV-specific CRISPR/ Cas9 plasmid to delete EBV and observed a dramatic decrease in cell viability, KSHV genome copy number, and LANA expression. This phenotype was reversed by expressing Epstein-Barr nuclear antigen 1 (EBNA-1) in trans, even though EBNA-1 and LANA do not colocalize in infected cells. This work reveals that EBV EBNA-1 plays an essential role in the pathogenesis of PEL by increasing KSHV viral load and LANA expression.O ne almost never finds two different viruses in the same cell. SignificancePrimary effusion lymphoma (PEL) is a B cell lymphoma; the prognosis is poor, with a median survival around 6 months. PEL is always associated with the presence of Kaposi's sarcomaassociated herpesvirus and in most cases is coinfected with Epstein-Barr virus (EBV); however, the role of EBV in the pathogenesis of the tumor is still not clear. This study demonstrates the intricate interaction between the two herpesviruses, which exacerbate tumorigenesis by mutually reinforcing the persistence of each latent genome and by altering cell proliferation. It establishes curing EBV and inhibiting Epstein-Barr nuclear antigen 1 as a potential treatment for PEL.

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“…It is likely that there is strong selection for recombination events that lead to a TR number similar to that in the virus. At least 16 TR elements are likely necessary for optimal KSHV episome maintenance (50).…”

Section: Discussionmentioning

confidence: 99%

Latency-Associated Nuclear Antigen E3 Ubiquitin Ligase Activity Impacts Gammaherpesvirus-Driven Germinal Center B Cell Proliferation

Cerqueira

Tan

et al. 2016

J Virol

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Viruses 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 (EC 5 S mLANA ) complex and mLANA's E3 ligase activity on host NF-B 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. A s obligatory intracellular parasites, viruses have evolved mechanisms to modulate ubiquitination, which is an essential regulatory mechanism in eukaryotes, controlling a wide range of cellular pathways. Ubiquitination occurs through a threeenzyme cascade involving an E1 ubiquitin-activating enzyme, an E2 ubiquitin-conjugating enzyme, and an E3 ubiquitin ligase enzyme (1). E3 ligases bind to the E2-ubiquitin intermediate and the substrate, catalyzing the transfer of ubiquitin to the substrate target lysine. Many E3 ligases have been described, such as Cullin 5-RING E3 ligases (CRL5), also known as Elongin BC/Cullin 5/SOCS (EC 5 S) E3 ligases. They are multisubunit complexes containing a scaffold protein (Cullin 5) attached to a RING finger protein (Rbx) (Cullin 5-Rbx module), an adaptor heterodimer (Elongin B/C), and a substrate recognition protein (suppressor of cytokine signaling [SOCS] box protein). The last component bridges the substrate of ubiquitination and the E3 ligase complex by interacting with Elongin B/C and Cullin 5 through a SOCS box motif (2-4). IMPORTANCE The 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 virusCertain viruses encode proteins with SOCS box motifs to hijack the components of cellular E3 ligases, thus modulating the ubiquitination pathway. Examples are latency-associated nuclear antigen (LANA) of Kaposi's sarcoma-associated herpesvirus (KSHV) (5, 6) and murid he...

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Identification of Properties of the Kaposi's Sarcoma-Associated Herpesvirus Latent Origin of Replication That Are Essential for the Efficient Establishment and Maintenance of Intact Plasmids

Cited by 12 publications

References 63 publications

Kaposi’s sarcoma–associated herpesvirus stably clusters its genomes across generations to maintain itself extrachromosomally

Kaposi’s sarcoma–associated herpesvirus stably clusters its genomes across generations to maintain itself extrachromosomally

Epstein–Barr virus enhances genome maintenance of Kaposi sarcoma-associated herpesvirus

Latency-Associated Nuclear Antigen E3 Ubiquitin Ligase Activity Impacts Gammaherpesvirus-Driven Germinal Center B Cell Proliferation

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