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.
journal_name
Nat Communjournal_title
Nature communicationsauthors
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 Mdoi
10.1038/ncomms12037subject
Has Abstractpub_date
2016-06-29 00:00:00pages
12037issn
2041-1723pii
ncomms12037journal_volume
7pub_type
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