Post-translational Regulation of FNIP1 Creates a Rheostat for the Molecular Chaperone Hsp90.
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
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
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
29 01 2019
29 01 2019
Historique:
received:
01
11
2018
revised:
12
12
2018
accepted:
04
01
2019
entrez:
31
1
2019
pubmed:
31
1
2019
medline:
14
3
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 30699359
pii: S2211-1247(19)30027-0
doi: 10.1016/j.celrep.2019.01.018
pmc: PMC6370319
mid: NIHMS1519903
pii:
doi:
Substances chimiques
Carrier Proteins
0
FNIP1 protein, human
0
HSP90 Heat-Shock Proteins
0
Nuclear Proteins
0
Phosphoserine
17885-08-4
Casein Kinase II
EC 2.7.11.1
Phosphoprotein Phosphatases
EC 3.1.3.16
protein phosphatase 5
EC 3.1.3.16
Proteasome Endopeptidase Complex
EC 3.4.25.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1344-1356.e5Subventions
Organisme : CCR NIH HHS
ID : HHSN261200800001C
Pays : United States
Organisme : NCI NIH HHS
ID : HHSN261200800001E
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM124256
Pays : United States
Informations de copyright
Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.
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