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

Author

Listed:
  • Mark R. Woodford

    (SUNY Upstate Medical University
    Cancer Research Institute, SUNY Upstate Medical University)

  • Diana M. Dunn

    (SUNY Upstate Medical University
    Cancer Research Institute, SUNY Upstate Medical University
    SUNY Upstate Medical University)

  • Adam R. Blanden

    (Cancer Research Institute, SUNY Upstate Medical University
    SUNY Upstate Medical University)

  • Dante Capriotti

    (SUNY Upstate Medical University
    Cancer Research Institute, 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
    SUNY Upstate Medical University)

  • Dimitra Bourboulia

    (SUNY Upstate Medical University
    Cancer Research Institute, SUNY Upstate Medical University
    SUNY Upstate Medical University)

  • Laura S. Schmidt

    (Basic Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research
    Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute)

  • W. Marston Linehan

    (Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute)

  • Gennady Bratslavsky

    (SUNY Upstate Medical University
    Cancer Research Institute, SUNY Upstate Medical University)

  • Mehdi Mollapour

    (SUNY Upstate Medical University
    Cancer Research Institute, SUNY Upstate Medical University
    SUNY Upstate Medical University)

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.

Suggested Citation

  • 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, 2016. "The FNIP co-chaperones decelerate the Hsp90 chaperone cycle and enhance drug binding," Nature Communications, Nature, vol. 7(1), pages 1-15, November.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12037
    DOI: 10.1038/ncomms12037
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