The FNIP co-chaperones decelerate the Hsp90 chaperone cycle and enhance drug binding

Mark R. Woodford, Diana M. Dunn, Adam R. Blanden, Dante Capriotti, David Loiselle, Chrisostomos Prodromou, Barry Panaretou, Philip F. Hughes, Aaron Smith, Wendi Ackerman, Timothy A. Haystead, Stewart N. Loh, Dimitra Bourboulia, Laura S. Schmidt, W. Marston Linehan, Gennady Bratslavsky and Mehdi Mollapour ()
Additional contact information
Mark R. Woodford: SUNY Upstate Medical University
Diana M. Dunn: SUNY Upstate Medical University
Adam R. Blanden: Cancer Research Institute, SUNY Upstate Medical University
Dante Capriotti: SUNY Upstate Medical University
David Loiselle: Duke University Medical Center
Chrisostomos Prodromou: Genome Damage and Stability Centre, University of Sussex
Barry Panaretou: Institute of Pharmaceutical Science, King’s College London
Philip F. Hughes: Duke University Medical Center
Aaron Smith: Duke University Medical Center
Wendi Ackerman: Health Sciences Library, SUNY Upstate Medical University
Timothy A. Haystead: Duke University Medical Center
Stewart N. Loh: Cancer Research Institute, SUNY Upstate Medical University
Dimitra Bourboulia: SUNY Upstate Medical University
Laura S. Schmidt: Basic Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research
W. Marston Linehan: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute
Gennady Bratslavsky: SUNY Upstate Medical University
Mehdi Mollapour: SUNY Upstate Medical University

Nature Communications, 2016, vol. 7, issue 1, 1-15

Abstract: Abstract Heat shock protein-90 (Hsp90) is an essential molecular chaperone in eukaryotes involved in maintaining the stability and activity of numerous signalling proteins, also known as clients. Hsp90 ATPase activity is essential for its chaperone function and it is regulated by co-chaperones. Here we show that the tumour suppressor FLCN is an Hsp90 client protein and its binding partners FNIP1/FNIP2 function as co-chaperones. FNIPs decelerate the chaperone cycle, facilitating FLCN interaction with Hsp90, consequently ensuring FLCN stability. FNIPs compete with the activating co-chaperone Aha1 for binding to Hsp90, thereby providing a reciprocal regulatory mechanism for chaperoning of client proteins. Lastly, downregulation of FNIPs desensitizes cancer cells to Hsp90 inhibitors, whereas FNIPs overexpression in renal tumours compared with adjacent normal tissues correlates with enhanced binding of Hsp90 to its inhibitors. Our findings suggest that FNIPs expression can potentially serve as a predictive indicator of tumour response to Hsp90 inhibitors.

Date: 2016
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DOI: 10.1038/ncomms12037

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