A Non-Canonical Function of Gβ as a Subunit of E3 Ligase in Targeting GRK2 Ubiquitylation

G protein-coupled receptors (GPCRs) comprise the largest family of cell surface receptors, regulate a wide range of physiological processes, and are the major targets of pharmaceutical drugs. Canonical signaling from GPCRs is relayed to intracellular effector proteins by trimeric G proteins, composed of α, β, and γ subunits (Gαβγ). Here, we report that G protein β subunits (Gβ) bind to DDB1 and that Gβ2 targets GRK2 for ubiquitylation by the DDB1-CUL4A-ROC1 ubiquitin ligase. Activation of GPCR results in PKA-mediated phosphorylation of DDB1 at Ser645 and its dissociation from Gβ2, leading to increase of GRK2 protein. Deletion of Cul4a results in cardiac hypertrophy in male mice that can be partially rescued by the deletion of one Grk2 allele. These results reveal a non-canonical function of the Gβ protein as a ubiquitin ligase component and a mechanism of feedback regulation of GPCR signaling. [Display omitted] •Gβ has a non-canonical role as a substrate recruiter of E3 ubiquitin ligase•Gβ2-DDB1-CUL4-ROC1 is a ubiquitin ligase targeting GRK2•β-AR signaling regulates GRK2 via PKA-mediated DDB1 phosphorylation•Deleting one Grk2 allele partially rescued heart hypertrophy in Cul4a-null mice G protein-coupled receptors (GPCRs) regulate a wide range of physiological processes and are relayed by trimeric G proteins, composed of α, β, and γ subunits. Zha et al. show a non-canonical function of the Gβ protein as a ubiquitin ligase component and a mechanism of feedback regulation of GPCR signaling.