Kaposi's Sarcoma-Associated Herpesvirus-Encoded Latency-Associated Nuclear Antigen Modulates K1 Expression through Its
            <i>cis</i>
            -Acting Elements within the Terminal Repeats

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Kaposi's sarcoma-associated herpesvirus (KSHV) persists as episomes in infected cells by circularizing at the terminal repeats (TRs).Kaposi's sarcoma-associated herpesvirus (KSHV), discovered using a subtractive hybridization technique from the Kaposi sarcoma lesions, is also associated with at least two lymphoproliferative diseases, primary effusion lymphoma (PEL) and multicentric Castleman's disease (9-11, 17, 54, 59). KSHV persists as multicopy episomal DNA in infected cells with the expression of a small subset of genes (18,34,55,65). Expression of the latency-associated nuclear antigen (LANA) is considered one of the crucial signatures of KSHV infection. Serum from KSHV-positive patients was initially used for the detection of LANA in infected cells (16,32). LANA is a large nuclear protein detected in a punctate pattern in KSHV-infected cells (37,48). LANA dots, which roughly correspond to the number of KSHV episomal copies, range from 15 to 120 per cell (13, 23). Detection of LANA and KSHV genomic DNA in an immunofluorescent in situ hybridization assay on chromosome spreads of KSHV-infected cells showed perfect colocalization of genomic DNA with LANA dots, suggesting the involvement of LANA in episomal tethering (13).The role of LANA in the persistence of the KSHV genome was evaluated using the 33-kb left-end Z6 cosmid of KSHV in BJAB cells expressing LANA under G418 selection (4). Z6 cosmid DNA efficiently persisted in LANA-expressing cells,

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confidence: 99%

The Minimal Replicator Element of the Kaposi's Sarcoma-Associated Herpesvirus Terminal Repeat Supports Replication in a Semiconservative and Cell-Cycle-Dependent Manner

Verma

Choudhuri

Robertson

2007

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“…Epstein-Barr Virus (EBV) nuclear antigen 1 (EBNA-1) and latency-associated nuclear antigen 1 (LANA-1), from Kaposi's sarcoma-associated herpesvirus (KSHV), are major latency proteins of these two gammaherpesviruses that are essential for maintaining viral episomes in infected cells (21,22). Independent studies suggest that both proteins have evolved mechanisms to remain largely invisible to the immune system, which could otherwise eliminate latently infected cells (8,9,19,25).…”

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confidence: 99%

“…Taken together with the surprising observation that fusion of the 5 untranslated region (UTR) of the c-myc mRNA to the 5 UTR of GAr-carrying mRNAs specifically inactivates the effect of the GAr, these results indicate that the GAr targets components of the translation initiation process. We propose a model in which the nascent GAr peptide delays the assembly of the initiation complex on its own mRNA.Epstein-Barr Virus (EBV) nuclear antigen 1 (EBNA-1) and latency-associated nuclear antigen 1 (LANA-1), from Kaposi's sarcoma-associated herpesvirus (KSHV), are major latency proteins of these two gammaherpesviruses that are essential for maintaining viral episomes in infected cells (21,22). Independent studies suggest that both proteins have evolved mechanisms to remain largely invisible to the immune system, which could otherwise eliminate latently infected cells (8,9,19,25).…”

mentioning

confidence: 99%

mRNA Translation Regulation by the Gly-Ala Repeat of Epstein-Barr Virus Nuclear Antigen 1

Apcher

Komarova

Daskalogianni

et al. 2009

The glycine-alanine repeat (GAr) sequence of the Epstein-Barr virus-encoded EBNA-1 prevents presentation of antigenic peptides to major histocompatibility complex class I molecules. This has been attributed to its capacity to suppress mRNA translation in cis. However, the underlying mechanism of this function remains largely unknown. Here, we have further investigated the effect of the GAr as a regulator of mRNA translation. Introduction of silent mutations in each codon of a 30-amino-acid GAr sequence does not significantly affect the translation-inhibitory capacity, whereas minimal alterations in the amino acid composition have strong effects, which underscores the observation that the amino acid sequence and not the mRNA sequence mediates GAr-dependent translation suppression. The capacity of the GAr to repress translation is dose and position dependent and leads to a relative accumulation of preinitiation complexes on the mRNA. Taken together with the surprising observation that fusion of the 5 untranslated region (UTR) of the c-myc mRNA to the 5 UTR of GAr-carrying mRNAs specifically inactivates the effect of the GAr, these results indicate that the GAr targets components of the translation initiation process. We propose a model in which the nascent GAr peptide delays the assembly of the initiation complex on its own mRNA.Epstein-Barr Virus (EBV) nuclear antigen 1 (EBNA-1) and latency-associated nuclear antigen 1 (LANA-1), from Kaposi's sarcoma-associated herpesvirus (KSHV), are major latency proteins of these two gammaherpesviruses that are essential for maintaining viral episomes in infected cells (21,22). Independent studies suggest that both proteins have evolved mechanisms to remain largely invisible to the immune system, which could otherwise eliminate latently infected cells (8,9,19,25). These mechanisms act in cis and are mediated via an internal repeat region. In the case of EBNA-1 this region consists of an N-terminal glycine-alanine repeat (GAr), and for LANA-1 the region consists of a glutamine-glutamate-aspartate central repeat (QED-CR). Although the two domains do not share amino acid homology, both retard their own synthesis to reduce the production of defective ribosomal products that can be processed for the major histocompatibility complex (MHC) class I-restricted antigen presentation pathway (23, 24), highlighting the importance of translation control in regulating MHC class I-restricted antigen presentation. To compensate for their low rates of synthesis, both proteins also have slow turnover rates (4, 8).Regulation of translation for most prokaryotic and eukaryotic mRNAs occurs at the level of initiation, but there are examples where regulation of protein synthesis depends on the elongation stage (17). The two main types of translation initiation are the classic cap-dependent and the less frequent cap-independent translation mechanisms (5,7,11,14,16). In the former, the preinitiation complex is formed around the cap structure in the 5Ј untranslated region (UTR) of the message, whereas i...

“…LANA, encoded by open reading frame 73 (ORF73), is the major latent protein expressed in all forms of KSHV-associated malignancies. LANA is a multifunctional protein which has the ability to (i) associate with cellular chromatin to maintain the viral episome (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28), (ii) activate or repress transcription (9,(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42), (iii) subvert tumor suppressors (38,40,(43)(44)(45), (iv) stimulate cellular transformation (16,34,(46)(47)(48)(49)(50)(51), and (v) block apoptosis (9,49,(52)(53)(54)…”

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confidence: 99%

Kaposi's Sarcoma-Associated Herpesvirus-Encoded LANA Contributes to Viral Latent Replication by Activating Phosphorylation of Survivin

Jha

Verma

et al. 2014

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Kaposi's sarcoma-associated herpesvirus (KSHV) is a human gammaherpesvirus casually linked to Kaposi's sarcoma (KS), multicentric Castleman's disease (MCD), and primary effusion lymphoma (PEL). Previously, we showed that LANA encoded by KSHV upregulates expression of survivin, a member of the inhibitor of apoptosis (IAP) family. This leads to an increase in the rate of cell proliferation of KSHV-infected B cells. LANA is required for tethering of the KSHV episome to the host chromosomes and efficiently segregates the viral genomes into dividing tumor cells. Here we show that LANA interacts with Aurora kinase B (AK-B) and induces phosphorylation of survivin at residue T34. Phosphorylation of survivin specifically on residue T34 enhances the activity of p300 and inhibits the activity of histone deacetylase 1 (HDAC-1), which then leads to an increase in acetylation of histone H3 on the viral genome. Phosphorylation of survivin specifically on residue T34 upregulates the activities of histone acetyltransferases and deacetylases, which then leads to an increase in viral copy number in KSHV-infected B cells. This results in a boost of KSHV replication in latently infected B-lymphoma cells. The studies showed that LANA can also function to regulate viral replication prior to mitosis of the latently infected cells, suggesting that LANA possesses a novel role in regulating KSHV replication in infected B cells. IMPORTANCE