Feedback inhibition of cAMP effector signaling by a chaperone-assisted ubiquitin system.
Animals
Cyclic AMP
/ metabolism
Cyclic AMP-Dependent Protein Kinase Catalytic Subunits
/ metabolism
Feedback, Physiological
/ drug effects
Fibroblasts
HEK293 Cells
HSP70 Heat-Shock Proteins
/ antagonists & inhibitors
Hippocampus
/ pathology
Holoenzymes
/ metabolism
Humans
Leupeptins
/ pharmacology
Mice
Mice, Inbred C57BL
Molecular Chaperones
/ metabolism
Phosphorylation
Primary Cell Culture
Protein Binding
/ drug effects
Proteolysis
/ drug effects
Purine Nucleosides
/ pharmacology
Signal Transduction
/ drug effects
Spinocerebellar Ataxias
/ genetics
Ubiquitin-Protein Ligases
/ genetics
Ubiquitination
/ physiology
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
12 06 2019
12 06 2019
Historique:
received:
26
09
2018
accepted:
12
04
2019
entrez:
14
6
2019
pubmed:
14
6
2019
medline:
6
7
2019
Statut:
epublish
Résumé
Activation of G-protein coupled receptors elevates cAMP levels promoting dissociation of protein kinase A (PKA) holoenzymes and release of catalytic subunits (PKAc). This results in PKAc-mediated phosphorylation of compartmentalized substrates that control central aspects of cell physiology. The mechanism of PKAc activation and signaling have been largely characterized. However, the modes of PKAc inactivation by regulated proteolysis were unknown. Here, we identify a regulatory mechanism that precisely tunes PKAc stability and downstream signaling. Following agonist stimulation, the recruitment of the chaperone-bound E3 ligase CHIP promotes ubiquitylation and proteolysis of PKAc, thus attenuating cAMP signaling. Genetic inactivation of CHIP or pharmacological inhibition of HSP70 enhances PKAc signaling and sustains hippocampal long-term potentiation. Interestingly, primary fibroblasts from autosomal recessive spinocerebellar ataxia 16 (SCAR16) patients carrying germline inactivating mutations of CHIP show a dramatic dysregulation of PKA signaling. This suggests the existence of a negative feedback mechanism for restricting hormonally controlled PKA activities.
Identifiants
pubmed: 31189917
doi: 10.1038/s41467-019-10037-y
pii: 10.1038/s41467-019-10037-y
pmc: PMC6561907
doi:
Substances chimiques
HSP70 Heat-Shock Proteins
0
Holoenzymes
0
Leupeptins
0
Molecular Chaperones
0
Purine Nucleosides
0
VER 155008
0
Cyclic AMP
E0399OZS9N
STUB1 protein, human
EC 2.3.2.27
Stub1 protein, mouse
EC 2.3.2.27
Ubiquitin-Protein Ligases
EC 2.3.2.27
Cyclic AMP-Dependent Protein Kinase Catalytic Subunits
EC 2.7.11.11
benzyloxycarbonylleucyl-leucyl-leucine aldehyde
RF1P63GW3K
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Video-Audio Media
Langues
eng
Sous-ensembles de citation
IM
Pagination
2572Subventions
Organisme : Austrian Science Fund FWF
ID : P 30441
Pays : Austria
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