The FNIP co-chaperones decelerate the Hsp90 chaperone cycle and enhance drug binding.
The FNIP co-chaperones decelerate the Hsp90 chaperone cycle and enhance drug binding.
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DOI：
10.1038/ncomms12037
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发表时间：
2016-06-29
影响因子：
16.6
通讯作者：
Mollapour M
中科院分区：
文献类型：
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作者：
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
热休克蛋白 90 (Hsp90) 是真核生物中重要的分子伴侣，参与维持众多信号蛋白（也称为客户端）的稳定性和活性。 Hsp90 ATP 酶活性对于其伴侣功能至关重要，并且受到辅助伴侣的调节。在这里，我们表明肿瘤抑制因子 FLCN 是一种 Hsp90 客户蛋白，其结合伴侣 FNIP1/FNIP2 作为共伴侣发挥作用。 FNIP 减缓伴侣循环，促进 FLCN 与 Hsp90 相互作用，从而确保 FLCN 稳定性。 FNIP 与激活辅助伴侣 Aha1 竞争与 Hsp90 的结合，从而为客户蛋白的伴侣提供相互调节机制。最后，FNIP 的下调使癌细胞对 Hsp90 抑制剂不敏感，而与邻近正常组织相比，肾肿瘤中 FNIP 的过度表达与 Hsp90 与其抑制剂的结合增强相关。我们的研究结果表明，FNIP 表达有可能作为肿瘤对 Hsp90 抑制剂反应的预测指标。 Hsp90 是多种肿瘤发生驱动因素的折叠、稳定性和活性所必需的。作者在此表明，卵泡素相互作用蛋白 (FNIP) 1 和 2 的表达与细胞对 Hsp90 抑制剂的反应相关，它们是 Hsp90 的共伴侣，通过抑制其 ATP 酶活性发挥作用。
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. Hsp90 is required for the folding, stability and activity of several drivers of oncogenesis. Here the authors show that Folliculin-interacting proteins (FNIP) 1 and 2, whose expression correlates with the cellular response to Hsp90 inhibitors, are co-chaperones of Hsp90 that function by inhibiting its ATPase activity.