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

Published online

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Woodford, MR; Dunn, DM; Blanden, AR; Capriotti, D; Loiselle, D; Prodromou, C; Panaretou, B; Hughes, PF; Smith, A; Ackerman, W; Haystead, TA; Loh, SN; Bourboulia, D; Schmidt, LS; Marston Linehan, W; Bratslavsky, G; Mollapour, M

Published Date

  • June 29, 2016

Published In

Volume / Issue

  • 7 /

Start / End Page

  • 12037 -

PubMed ID

  • 27353360

Pubmed Central ID

  • 27353360

Electronic International Standard Serial Number (EISSN)

  • 2041-1723

Digital Object Identifier (DOI)

  • 10.1038/ncomms12037

Language

  • eng

Conference Location

  • England