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First published online 30 July 2003
doi: 10.1242/jcs.00691

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KSHV vFLIP binds to IKK- to activate IKK

Nigel Field¹, Walter Low^1,*, Mark Daniels¹, Steven Howell², Laurent Daviet³, Chris Boshoff⁴ and Mary Collins^1,

¹ Department of Immunology and Molecular Pathology, University College London, Windeyer Institute, 46 Cleveland St, London W1T 2AH, UK
² National Institute for Medical Research, Laboratory of Protein Structure, The Ridgeway, Mill Hill, London NW7 1AA, UK
³ Hybrigenics, 3-5 Impasse Reille, 75014 Paris, France
⁴ Cancer Research UK Viral Oncology Group, Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, UK

Author for correspondence (e-mail: mary.collins{at}ucl.ac.uk)

Accepted 28 May 2003

When expressed in heterologous cells, the viral FLIP protein (vFLIP) of Kaposi's-sarcoma-associated herpesvirus (KSHV) has been reported both to block Fas-mediated apoptosis and to activate the NF-B activation pathway by interaction with IB kinase (IKK). In a yeast-two-hybrid screen, we identified IKK as an interacting partner of vFLIP. We expressed fragments of IKK in mammalian cells and bacteria, and identified the central CCR3/4 (amino acids 150-272) as the vFLIP binding region. To investigate the proteins interacting with vFLIP in a KSHV-infected primary effusion lymphoma (PEL) cell line, we immunoprecipitated vFLIP and identified four associated proteins by mass spectrometry: IKK components IKK, ß and , and the chaperone, Hsp90. Using gel filtration chromatography, we demonstrated that a single population of vFLIP in the cytoplasm of PEL cells co-eluted and co-precipitated with an activated IKK complex. An inhibitor of Hsp90, geldanamycin, inhibited IKK's kinase activity induced by vFLIP and killed PEL cells, suggesting that vFLIP activation of IKK contributes to PEL cell survival.

Key words: KSHV, vFLIP, IKK, Hsp90

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