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

Cell Rep. 2019 Jan 29;26(5):1344-1356.e5. doi: 10.1016/j.celrep.2019.01.018.


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.

Keywords: BHD; Birt-Hogg-Dubé syndrome; FNIP1; Hsp90; O-GlcNAcylation; PP5; co-chaperone; folliculin-interacting protein 1; heat shock protein 90; serine/threonine protein phosphatase 5.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carrier Proteins / metabolism*
  • Casein Kinase II / metabolism
  • Glycosylation
  • HEK293 Cells
  • HSP90 Heat-Shock Proteins / metabolism*
  • Humans
  • Models, Biological
  • Nuclear Proteins / metabolism
  • Phosphoprotein Phosphatases / metabolism
  • Phosphorylation
  • Phosphoserine / metabolism
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Binding
  • Protein Processing, Post-Translational*
  • Ubiquitination


  • Carrier Proteins
  • FNIP1 protein, human
  • HSP90 Heat-Shock Proteins
  • Nuclear Proteins
  • Phosphoserine
  • Casein Kinase II
  • Phosphoprotein Phosphatases
  • protein phosphatase 5
  • Proteasome Endopeptidase Complex