TY - JOUR
T1 - A Non-Canonical Function of Gβ as a Subunit of E3 Ligase in Targeting GRK2 Ubiquitylation
AU - Zha, Zhengyu
AU - Han, Xiaoran
AU - Smith, Matthew D.
AU - Liu, Yang
AU - Giguère, Patrick M.
AU - Kopanja, Dragana
AU - Raychaudhuri, Pradip
AU - Siderovski, David P.
AU - Guan, Kun Liang
AU - Lei, Qun Ying
AU - Xiong, Yue
PY - 2015/6/4
Y1 - 2015/6/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84931091401&partnerID=8YFLogxK
U2 - 10.1016/j.molcel.2015.04.017
DO - 10.1016/j.molcel.2015.04.017
M3 - Article
C2 - 25982117
AN - SCOPUS:84931091401
VL - 58
SP - 794
EP - 803
JO - Molecular Cell
JF - Molecular Cell
SN - 1097-2765
IS - 5
ER -