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Regulation of Kaposi's sarcoma -associated herpesvirus (KSHV) lytic gene expression by viral transactivator RTA and cellular repressor K-RBP

Zhilong Yang, University of Nebraska - Lincoln

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV) is a newly identified human herpesvirus and the etiologic agent of Kaposi's sarcoma (KS). KSHV can establish latency and be reactivated to lytic replication in infected cells. The viral replication and transcriptional activator (RTA) is the key protein that initiates KSHV lytic replication by activating the expression of many KSHV lytic genes and DNA replication. Understanding how RTA transactivates target genes and is modulated by cellular factors is pivotal to elucidate the mechanism by which KSHV regulates its latent and lytic replication cycles. ^ KSHV-RTA binding protein (K-RBP) is a cellular RTA interacting protein. It contains a Kruppel-associated box (KRAB) at the N terminus and 12 adjacent zinc finger motifs. K-RBP is a transcriptional repressor and down-regulate RTA-mediated transactivation of several KSHV promoters including ORF57. The KRAB domain is the repression domain and the zinc finger domain binds DNA with high GC content. Moreover, K-RBP binds to and suppresses KSHV ORF57 promoter in a GC-rich element-dependent manner. K-RBP also competes with RTA in binding to ORF57 promoter. In addition, the zinc finger domain of K-RBP is sufficient to suppress RTA-mediated transactivation of ORF57 promoter suggesting an important role of the DNA-binding activity of K-RBP in repressing RTA-mediated transactivation. K-RBP is also a negative regulator of RTA-mediated KSHV lytic replication. ^ Further studies show that RTA promotes K-RBP degradation through a proteasome-dependent pathway. RTA also stimulates degradation of several other repressors. The ability of RTA to induce degradation correlates with its ability to transactivate target promoter. These results suggest that KSHV RTA stimulates the turnover of repressors to favor viral lytic gene expression and lytic replication. ^ Together these studies suggest that the cellular transcriptional repressor K-RBP suppresses RTA-mediated transactivation and KSHV reactivation, while RTA promotes the degradation of the repressor to stimulate KSHV lytic replication. Finally, these studies suggest that the establishment of latency or lytic replication involves a regulatory loop between RTA and the repressors. ^

Subject Area

Biology, Molecular|Biology, Microbiology|Biology, Virology

Recommended Citation

Yang, Zhilong, "Regulation of Kaposi's sarcoma -associated herpesvirus (KSHV) lytic gene expression by viral transactivator RTA and cellular repressor K-RBP" (2007). ETD collection for University of Nebraska - Lincoln. AAI3284223.
http://digitalcommons.unl.edu/dissertations/AAI3284223

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