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IL-10 promoter transactivation by the viral K-RTA protein involves the host-cell transcription factors Specificity Protein 1 and 3.

IL-10 promoter transactivation by the viral K-RTA protein involves the host-cell transcription factors Specificity Protein 1 and 3.
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Miyazawa M, Noguchi K, Kujirai M, Katayama K, Yamagoe S, Sugimoto Y,


Miyazawa M, Noguchi K, Kujirai M, Katayama K, Yamagoe S, Sugimoto Y, (click to view)

Miyazawa M, Noguchi K, Kujirai M, Katayama K, Yamagoe S, Sugimoto Y,

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The Journal of biological chemistry 2017 11 28() pii 10.1074/jbc.M117.802900

Abstract

Kaposi’s sarcoma-associated herpesvirus (KSHV)/human herpesvirus-8 (HHV-8) causes a persistent infection, presenting latent and lytic replication phases during its life cycle. KSHV-related diseases are associated with deregulated expression of inflammatory cytokines, including IL-6 and IL-10, but the mechanisms underlying this dysregulation are unclear. Herein, we report a molecular mechanism for KSHV-induced IL-10 gene expression. KSHV replication and transcription activator (K-RTA) is a molecular switch for the initiation of expression of viral lytic genes, and we describe, for the first time, that K-RTA significantly activates the promoter of the human IL-10 gene. Of note, mutations involving a basic region of K-RTA reduced the association of K-RTA with the IL-10 promoter. Moreover, the host-cell transcription factors Specificity Proteins (SP) 1 and 3 play a pivotal cooperative role in K-RTA-mediated transactivation of the IL-10 promoter. K-RTA can interact with SP1 and SP3 directly in vitro, and electrophoresis mobility shift assays (EMSAs) revealed co-operative interaction involving K-RTA, SP1 and SP3 in binding to the IL-10 promoter. As DNase I footprinting assays indicated that K-RTA did not affect SP3-binding to the IL-10 promoter, SP3 can function to recruit K-RTA to the IL-10 promoter. These findings indicate that K-RTA can directly contribute to IL-10 upregulation via a functional interplay with the cellular transcription factors SP1 and SP3.

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