Feedback inhibition of cAMP effector signaling by a chaperone-assisted ubiquitin system

Laura Rinaldi, Rossella Delle Donne, Bruno Catalanotti, Omar Torres-Quesada, Florian Enzler, Federica Moraca, Robert Nisticò, Francesco Chiuso, Sonia Piccinin, Verena Bachmann, Herbert H Lindner, Corrado Garbi, Antonella Scorziello, Nicola Antonino Russo, Matthis Synofzik, Ulrich Stelzl, Lucio Annunziato, Eduard Stefan and Antonio Feliciello ()
Additional contact information
Laura Rinaldi: University Federico II
Rossella Delle Donne: University Federico II
Bruno Catalanotti: University Federico II
Omar Torres-Quesada: University of Innsbruck
Florian Enzler: University of Innsbruck
Federica Moraca: University Federico II
Robert Nisticò: University Tor Vergata
Francesco Chiuso: University Federico II
Sonia Piccinin: University Tor Vergata
Verena Bachmann: University of Innsbruck
Herbert H Lindner: Biocenter Medical University of Innsbruck
Corrado Garbi: University Federico II
Antonella Scorziello: University Federico II
Nicola Antonino Russo: I.R.C.S., BIOGEM, Ariano Irpino
Matthis Synofzik: University of Tübingen and German Center for Neurodegenerative Diseases (DZNE)
Ulrich Stelzl: University of Graz and BioTechMed-Graz
Lucio Annunziato: IRCCS SDN
Eduard Stefan: University of Innsbruck
Antonio Feliciello: University Federico II

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: 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.

Date: 2019
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-10037-y

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DOI: 10.1038/s41467-019-10037-y

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