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Hsp90 and Hsp40/Erdj3 are required for the expression and anti-apoptotic function of KSHV K1

Oncogene volume 29, pages 3532–3544 (2010)Cite this article

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Abstract

Kaposi sarcoma-associated herpesvirus (KSHV) is a member of the gammaherpesvirus family. It is the etiological agent of three different human cancers, Kaposi sarcoma (KS), primary effusion lymphoma (PEL) and multicentric Castleman disease. The far left end of the KSHV genome encodes a unique transmembrane glycoprotein called K1. K1 possesses the ability to transform rodent fibroblasts and block apoptosis. K1 has also been shown to activate the PI3K/Akt/mTOR pathway in different cells. Using tandem affinity purification, we identified heat shock protein 90β (Hsp90β) and endoplasmic reticulum-associated Hsp40 (Erdj3/DnaJB11), as cellular binding partners of K1. Interactions of K1 with Hsp90β and Hsp40 were confirmed by co-immunoprecipitation in both directions. Furthermore, K1 also interacted with the Hsp90α isoform. We report that small-interfering RNAs directed against Hsp90 and Hsp40/Erdj3, as well as pharmacological inhibitors of Hsp90, dramatically reduced K1 expression, suggesting that K1 is a client protein of these chaperones. In addition, both Hsp90 and Hsp40/Erdj3 were essential for K1's anti-apoptotic function. Finally, we report that the Hsp90 inhibitors, 17-AAG and 17-DMAG, can suppress the proliferation of KSHV-positive PEL cell lines and exhibited IC50 values of 50 nM and below.

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Acknowledgements

We thank Dr Prasanna Bhende for help with immunohistochemistry and cell-cycle analysis and Stuart Krall for technical assistance. We thank Dr Jae Jung for providing us with the anti-K1 antibody and members of the Damania and Dittmer lab for informative discussions. We also thank the UNC Proteomics Center for processing of the protein samples and subsequent mass spectroscopy analysis. BD is a Leukemia & Lymphoma Society Scholar, American Heart Association established investigator, and a Burroughs Wellcome Fund Investigator in Infectious Disease. This work was supported by grant CA096500 from NIH and a University of Pennsylvania CFAR pilot project grant (P30-AI045008) to BD. KWW was supported in part by NIAID training Grant T32-AI007001 and MSTP Grant T32-GM008719. BD is a Leukemia & Lymphoma Society Scholar and Burroughs Welcome Fund Investigator in Infectious Disease.

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  1. Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA

    K W Wen & B Damania

  2. Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC, USA

    K W Wen & B Damania

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Correspondence to B Damania.

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Wen, K., Damania, B. Hsp90 and Hsp40/Erdj3 are required for the expression and anti-apoptotic function of KSHV K1. Oncogene 29, 3532–3544 (2010). https://doi.org/10.1038/onc.2010.124

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