Post-translational regulation of FNIP1 creates a rheostat for the molecular chaperone Hsp90

Sager, Rebecca A, Woodford, Mark R, Backe, Sarah J, Makedon, Alan M, Baker-Williams, Alexander J, DiGregorio, Bryan T, Loiselle, David R, Haystead, Timothy A, Zachara, Natasha E, Prodromou, Chrisostomos, Bourboulia, Dimitra, Schmidt, Laura S, Linehan, W Marston, Bratslavsky, Gennady and Mollapour, Mehdi (2019) Post-translational regulation of FNIP1 creates a rheostat for the molecular chaperone Hsp90. Cell Reports, 26 (5). 1344-1356.e5. ISSN 2211-1247

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The molecular chaperone Hsp90 stabilizes and activates client proteins. Co-chaperones and post-translational modifications tightly regulate Hsp90 function and consequently lead to activation of clients. However, it is unclear whether this process occurs abruptly or gradually in the cellular context. We show that casein kinase-2 phosphorylation of the co-chaperone folliculin-interacting protein 1 (FNIP1) on priming serine-938 and subsequent relay phosphorylation on serine-939, 941, 946, and 948 promotes its gradual interaction with Hsp90. This leads to incremental inhibition of Hsp90 ATPase activity and gradual activation of both kinase and non-kinase clients. We further demonstrate that serine/threonine protein phosphatase 5 (PP5) dephosphorylates FNIP1, allowing the addition of O-GlcNAc (O-linked N-acetylglucosamine) to the priming serine-938. This process antagonizes phosphorylation of FNIP1, preventing its interaction with Hsp90, and consequently promotes FNIP1 lysine-1119 ubiquitination and proteasomal degradation. These findings provide a mechanism for gradual activation of the client proteins through intricate crosstalk of post-translational modifications of the co-chaperone FNIP1.

Item Type: Article
Keywords: heat shock protein 90, Hsp90 co-chaperone, FNIP1, folliculin-interacting protein 1, serine/threonine protein phosphatase 5, PP5O-GlcNAcylation, Birt-Hogg-Dubé syndrome, BHD
Schools and Departments: School of Life Sciences > Biochemistry
Subjects: Q Science > Q Science (General)
R Medicine
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Depositing User: Chrisostomos Prodromou
Date Deposited: 29 Apr 2019 13:37
Last Modified: 02 Jul 2019 06:47

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