TY - JOUR
T1 - Feedback inhibition of cAMP effector signaling by a chaperone-assisted ubiquitin system
AU - Rinaldi, Laura
AU - Delle Donne, Rossella
AU - Catalanotti, Bruno
AU - Torres-Quesada, Omar
AU - Enzler, Florian
AU - Moraca, Federica
AU - Nisticò, Robert
AU - Chiuso, Francesco
AU - Piccinin, Sonia
AU - Bachmann, Verena
AU - Lindner, Herbert H.
AU - Garbi, Corrado
AU - Scorziello, Antonella
AU - Russo, Nicola Antonino
AU - Synofzik, Matthis
AU - Stelzl, Ulrich
AU - Annunziato, Lucio
AU - Stefan, Eduard
AU - Feliciello, Antonio
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-019-10037-y
DO - 10.1038/s41467-019-10037-y
M3 - Article
C2 - 31189917
AN - SCOPUS:85067274974
VL - 10
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 2572
ER -