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 chaperonebound 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.

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.; Nistico', ROBERT GIOVANNI; Chiuso, Francesco; Piccinin, S.; Bachmann, V.; Lindner, H. H.; Garbi, C.; Scorziello, A.; Russo, N. A.; Synofzik, M.; Stelzl, U.; Annunziato, L.; Stefan, Eduard; Feliciello, A.. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 10:1(2019), p. 2572. [10.1038/s41467-019-10037-y]

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

Rinaldi L.;Delle Donne R.;Catalanotti B.;Moraca F.;NISTICO', ROBERT GIOVANNI;CHIUSO, FRANCESCO;Garbi C.;Scorziello A.;Annunziato L.;STEFAN, EDUARD;Feliciello A.
2019

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 chaperonebound 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.
2019
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.; Nistico', ROBERT GIOVANNI; Chiuso, Francesco; Piccinin, S.; Bachmann, V.; Lindner, H. H.; Garbi, C.; Scorziello, A.; Russo, N. A.; Synofzik, M.; Stelzl, U.; Annunziato, L.; Stefan, Eduard; Feliciello, A.. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 10:1(2019), p. 2572. [10.1038/s41467-019-10037-y]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/764802
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