Post-translational Regulation of FNIP1 Creates a Rheostat for the Molecular Chaperone Hsp90.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Sager, RA; Woodford, MR; Backe, SJ; Makedon, AM; Baker-Williams, AJ; DiGregorio, BT; Loiselle, DR; Haystead, TA; Zachara, NE; Prodromou, C; Bourboulia, D; Schmidt, LS; Linehan, WM; Bratslavsky, G; Mollapour, M

Published Date

  • January 29, 2019

Published In

Volume / Issue

  • 26 / 5

Start / End Page

  • 1344 - 1356.e5

PubMed ID

  • 30699359

Pubmed Central ID

  • PMC6370319

Electronic International Standard Serial Number (EISSN)

  • 2211-1247

Digital Object Identifier (DOI)

  • 10.1016/j.celrep.2019.01.018


  • eng

Conference Location

  • United States