Journal Article

DZNE-2020-07073

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Feedback inhibition of cAMP effector signaling by a chaperone-assisted ubiquitin system.

Rinaldi, L. ; Delle Donne, R. ; Catalanotti, B. ; Torres-Quesada, O. ; Enzler, F. ; Moraca, F. ; Nisticò, R. ; Chiuso, F. ; Piccinin, S. ; Bachmann, V. ; Lindner, H. H. ; Garbi, C. ; Scorziello, A. ; Russo, N. A. ; Synofzik, M.DZNE* ; Stelzl, U. ; Annunziato, L. ; Stefan, E. ; Feliciello, A. (Corresponding author)

2019
Nature Publishing Group UK [London]

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Please use a persistent id in citations: doi:10.1038/s41467-019-10037-y

Abstract: 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.

Keyword(s): Animals (MeSH) ; Cyclic AMP: metabolism (MeSH) ; Cyclic AMP-Dependent Protein Kinase Catalytic Subunits: metabolism (MeSH) ; Feedback, Physiological: drug effects (MeSH) ; Feedback, Physiological: physiology (MeSH) ; Fibroblasts (MeSH) ; HEK293 Cells (MeSH) ; HSP70 Heat-Shock Proteins: antagonists & inhibitors (MeSH) ; Hippocampus: pathology (MeSH) ; Holoenzymes: metabolism (MeSH) ; Humans (MeSH) ; Leupeptins: pharmacology (MeSH) ; Mice (MeSH) ; Mice, Inbred C57BL (MeSH) ; Molecular Chaperones: metabolism (MeSH) ; Phosphorylation (MeSH) ; Primary Cell Culture (MeSH) ; Protein Binding: drug effects (MeSH) ; Proteolysis: drug effects (MeSH) ; Purine Nucleosides: pharmacology (MeSH) ; Signal Transduction: drug effects (MeSH) ; Signal Transduction: physiology (MeSH) ; Spinocerebellar Ataxias: genetics (MeSH) ; Spinocerebellar Ataxias: pathology (MeSH) ; Ubiquitin-Protein Ligases: genetics (MeSH) ; Ubiquitin-Protein Ligases: metabolism (MeSH) ; Ubiquitination: physiology (MeSH) ; HSP70 Heat-Shock Proteins ; Holoenzymes ; Leupeptins ; Molecular Chaperones ; Purine Nucleosides ; VER 155008 ; Cyclic AMP ; STUB1 protein, human ; Stub1 protein, mouse ; Ubiquitin-Protein Ligases ; Cyclic AMP-Dependent Protein Kinase Catalytic Subunits ; benzyloxycarbonylleucyl-leucyl-leucine aldehyde

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Contributing Institute(s):

1. Parkinson Genetics (AG Gasser)

Research Program(s):

1. 345 - Population Studies and Genetics (POF3-345) (POF3-345)

Appears in the scientific report 2019

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Linked articles:

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Journal Article (Erratum/Correction) Rinaldi, L. ; Donne, R. D. ; Catalanotti, B. ; Torres-Quesada, O. ; Enzler, F. ; Moraca, F. ; Nisticò, R. ; Chiuso, F. ; Piccinin, S. ; Bachmann, V. ; Lindner, H. H. ; Garbi, C. ; Scorziello, A. ; Russo, N. A. ; Synofzik, M.DZNE* ; Stelzl, U. ; Annunziato, L. ; Stefan, E. ; Feliciello, A.
Author Correction: Feedback inhibition of cAMP effector signaling by a chaperone-assisted ubiquitin system.
Nature Communications 15(1), 4565 (2024) [10.1038/s41467-024-49118-y]2024   Files  Fulltext by Pubmed Central BibTeX | EndNote: XML, Text | RIS

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