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A nuclear role for Kaposi's sarcoma-associated herpesvirus-encoded K13 protein in gene regulation

Oncogene volume 27, pages 5243–5253 (2008)Cite this article

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV)-encoded viral FLICE inhibitory protein K13 interacts with a cytosolic IκB kinase (IKK) complex to activate nuclear factor-κB (NF-κB). We recently reported that K13 antagonizes KSHV lytic regulator RTA (replication and transcription activator) and blocks lytic replication, but spares RTA-induced viral interleukin-6 (vIL6). Here we report that K13 is also present in the nuclear compartment, a property not shared by its structural homologs. K13 interacts with and activates the nuclear IKK complex, and binds to the IκBα promoter. K13 mutants that are retained in the cytosol lack NF-κB activity. However, neither the IKKs nor NF-κB activation is required for nuclear localization of K13. Instead, this ability is dependent on a nuclear localization signal located in its N-terminal 40 amino acids. Finally, K13, along with p65/RelA, binds to the promoters of a number of KSHV lytic genes, including RTA, ORF57 and vGPCR, but not to the promoter of the vIL6 gene. Thus, K13 has an unexpected nuclear role in viral and cellular gene regulation and its differential binding to the promoters of lytic genes may not only contribute to the inhibition of KSHV lytic replication, but may also account for the escape of vIL6 from K13-induced transcriptional suppression.

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Acknowledgements

We thank Dr Inder Verma for providing the IKK-deficient MEFs, Dr Shao-Cong Sun for NEMO-deficient Jurkat cells and Dr Mary Collins for a K13 monoclonal antibody. This work was supported by grants from the National Institutes of Health (CA85177 and CA124621), the Leukemia and Lymphoma Society and the Mario Lemieux Foundation.

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Author notes

  1. H Matta and V Punj: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine, Division of Hematology-Oncology, Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    H Matta, V Punj, S Schamus, L Mazzacurati, A M Chen, R Song & P M Chaudhary

  2. Spang Translational Research Core Facility, Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    T Yang

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  1. H Matta
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Correspondence to P M Chaudhary.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Matta, H., Punj, V., Schamus, S. et al. A nuclear role for Kaposi's sarcoma-associated herpesvirus-encoded K13 protein in gene regulation. Oncogene 27, 5243–5253 (2008). https://doi.org/10.1038/onc.2008.150

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