Egr-1 regulates RTA transcription through a cooperative involvement of transcriptional regulators
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Authors
Sarkar, Roni
Verma, Subhash C.
Issue Date
2017
Type
Article
Language
Keywords
KSHV , lytic reactivation , RTA , Egr-1 , CBP
Alternative Title
Abstract
Kaposi's sarcoma associated herpesvirus (KSHV) regulates the host cellular environment to establish life-long persistent infection by manipulating cellular signaling pathways, with approximately 1-5% of cells undergoing lytic reactivation during the course of infection. Egr-1 (Early Growth Response Factor-1) is one such cellular transcription factor, which gets phosphorylated during the lytic phase of viral life cycle to perpetrate its function. This study demonstrates the mechanism of how Egr-1 mediates transcription of the immediate early gene, RTA (Replication and transcription activator), which is the lytic switch gene of KSHV. Egr-1 depleted KSHV infected cells exhibited reduced expression of RTA. Also, an increase in Egr1 phosphorylation led to a higher virion production, which was suppressed in the presence of p38 and Raf inhibitors. Reporter assays showed that coexpression of Egr1 and CBP (CREB-binding protein) enhances RTA promoter activity as compared to the expression of either Egr-1 or CBP alone. Binding of Egr-1 and CBP at RTA promoter was analyzed by chromatin immunoprecipitation assay (ChIP), which showed an enhanced accumulation during viral reactivation. Mutation in Egr-1 binding site of the RTA promoter eliminated Egr-1 response on promoter activation. Furthermore, de novo infection of THP-1 (monocytic) and HUVECs (endothelial) cells showed an upregulation of Egr-1 phosphorylation, whereas depletion of Egr-1 reduced the mRNA levels of RTA during primary infection. Together, these results demonstrate a cooperative role of Egr-1 and CBP in mediating RTA transcription, which significantly improves our understanding of the involvement of cellular factors controlling RTA transcription in KSHV pathogenesis.
Description
Citation
Sarkar, R., & Verma, S. C. (2017). Egr-1 regulates RTA transcription through a cooperative involvement of transcriptional regulators. Oncotarget, 8(53). doi:10.18632/oncotarget.20648
Publisher
License
Creative Commons Attribution 3.0 Unported
Journal
Volume
Issue
PubMed ID
ISSN
1949-2553