Format

Send to

Choose Destination
Nat Commun. 2016 Jun 29;7:12037. doi: 10.1038/ncomms12037.

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

Author information

1
Department of Urology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, New York 13210, USA.
2
Cancer Research Institute, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, New York 13210, USA.
3
Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, New York 13210, USA.
4
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
5
Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, UK.
6
Institute of Pharmaceutical Science, King's College London, London SE1 9NH, UK.
7
Health Sciences Library, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, New York 13210, USA.
8
Basic Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, USA.
9
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Bethesda, Maryland 20892, USA.

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.

PMID:
27353360
PMCID:
PMC4931344
DOI:
10.1038/ncomms12037
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center