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Comprehensive mapping and analysis of Kaposi's sarcoma-associated herpesvirus 3' UTRs identify differential posttranscriptional control of gene expression in lytic versus latent infection.

ABSTRACT: 3' untranslated regions (UTRs) are known to play an important role in posttranscriptional regulation of gene expression. Here we map the 3' UTRs of Kaposi's sarcoma-associated herpesvirus (KSHV) using next-generation RNA sequencing, 3' rapid amplification of cDNA ends (RACE), and tiled microarray analyses. Chimeric reporters containing the KSHV 3' UTRs show a general trend toward reduced gene expression under conditions of latent infection. Those 3' UTRs with a higher GC content are more likely to be associated with reduced gene expression. KSHV transcripts display an extensive use of shared polyadenylation sites allowing for partially overlapping 3' UTRs and regulatory activities. In addition, a subset of KSHV 3' UTRs is sufficient to convey increased gene expression under conditions of lytic infection. These results suggest a role for viral 3' UTRs in contributing to differential gene expression during latent versus lytic infection.

SUBMITTER: McClure LV

PROVIDER: S-EPMC3838127 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Comprehensive mapping and analysis of Kaposi's sarcoma-associated herpesvirus 3' UTRs identify differential posttranscriptional control of gene expression in lytic versus latent infection.

McClure Lydia V LV Kincaid Rodney P RP Burke James M JM Grundhoff Adam A Sullivan Christopher S CS

Journal of virology 20130925 23

3' untranslated regions (UTRs) are known to play an important role in posttranscriptional regulation of gene expression. Here we map the 3' UTRs of Kaposi's sarcoma-associated herpesvirus (KSHV) using next-generation RNA sequencing, 3' rapid amplification of cDNA ends (RACE), and tiled microarray analyses. Chimeric reporters containing the KSHV 3' UTRs show a general trend toward reduced gene expression under conditions of latent infection. Those 3' UTRs with a higher GC content are more likely ...[more]

PMID: 24067953

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Project description:UnlabelledKaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of commonly fatal malignancies of immunocompromised individuals, including primary effusion lymphoma (PEL) and Kaposi's sarcoma (KS). A hallmark of all herpesviruses is their biphasic life cycle-viral latency and the productive lytic cycle-and it is well established that reactivation of the KSHV lytic cycle is associated with KS pathogenesis. Therefore, a thorough appreciation of the mechanisms that govern reactivation is required to better understand disease progression. The viral protein replication and transcription activator (RTA) is the KSHV lytic switch protein due to its ability to drive the expression of various lytic genes, leading to reactivation of the entire lytic cycle. While the mechanisms for activating lytic gene expression have received much attention, how RTA impacts cellular function is less well understood. To address this, we developed a cell line with doxycycline-inducible RTA expression and applied stable isotope labeling of amino acids in cell culture (SILAC)-based quantitative proteomics. Using this methodology, we have identified a novel cellular protein (AT-rich interacting domain containing 3B [ARID3B]) whose expression was enhanced by RTA and that relocalized to replication compartments upon lytic reactivation. We also show that small interfering RNA (siRNA) knockdown or overexpression of ARID3B led to an enhancement or inhibition of lytic reactivation, respectively. Furthermore, DNA affinity and chromatin immunoprecipitation assays demonstrated that ARID3B specifically interacts with A/T-rich elements in the KSHV origin of lytic replication (oriLyt), and this was dependent on lytic cycle reactivation. Therefore, we have identified a novel cellular protein whose expression is enhanced by KSHV RTA with the ability to inhibit KSHV reactivation.ImportanceKaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of fatal malignancies of immunocompromised individuals, including Kaposi's sarcoma (KS). Herpesviruses are able to establish a latent infection, in which they escape immune detection by restricting viral gene expression. Importantly, however, reactivation of productive viral replication (the lytic cycle) is necessary for the pathogenesis of KS. Therefore, it is important that we comprehensively understand the mechanisms that govern lytic reactivation, to better understand disease progression. In this study, we have identified a novel cellular protein (AT-rich interacting domain protein 3B [ARID3B]) that we show is able to temper lytic reactivation. We showed that the master lytic switch protein, RTA, enhanced ARID3B levels, which then interacted with viral DNA in a lytic cycle-dependent manner. Therefore, we have added a new factor to the list of cellular proteins that regulate the KSHV lytic cycle, which has implications for our understanding of KSHV biology.

Dataset Information

Comprehensive mapping and analysis of Kaposi's sarcoma-associated herpesvirus 3' UTRs identify differential posttranscriptional control of gene expression in lytic versus latent infection.

Publications

Comprehensive mapping and analysis of Kaposi's sarcoma-associated herpesvirus 3' UTRs identify differential posttranscriptional control of gene expression in lytic versus latent infection.

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