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

Activation of G-protein coupled receptors elevates cAMP levels promoting dissociation of protein kinase A holoenzymes and release of catalytic subunits This results in phosphorylation of compartmentalized substrates that control central aspects of cell physiology. The mechanism of activation and signaling have been largely characterized. However, the modes of duanyu1529c inactivation by regulated proteolysis were unknown. Here, we identify a regulatory mechanism that precisely tunes duanyu1529c stability and downstream signaling. Following agonist stimulation, the recruitment of the chaperone-bound E3 ligase CHIP promotes ubiquitylation and proteolysis of thus attenuating cAMP signaling. Genetic inactivation of CHIP or pharmacological inhibition of HSP70 enhances duanyu1529c 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 signaling. This suggests the existence of a negative feedback mechanism for restricting hormonally controlled duanyu1529 activities.

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