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

Zhengyu Zha; Xiaoran Han; Matthew D. Smith; Yang Liu; Patrick M. Giguère; Dragana Kopanja; Pradip Raychaudhuri; David P. Siderovski; Kun Liang Guan; Qun Ying Lei; Yue Xiong

doi:10.1016/j.molcel.2015.04.017

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

Zhengyu Zha, Xiaoran Han, Matthew D. Smith, Yang Liu, Patrick M. Giguère, Dragana Kopanja, Pradip Raychaudhuri, David P. Siderovski, Kun Liang Guan, Qun Ying Lei, Yue Xiong

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Abstract

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.

Original language	English
Pages (from-to)	794-803
Number of pages	10
Journal	Molecular Cell
Volume	58
Issue number	5
DOIs	https://doi.org/10.1016/j.molcel.2015.04.017
State	Published - 4 Jun 2015

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@article{214f9d89dae34d64a81ca8f3552a2880,

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

abstract = "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.",

author = "Zhengyu Zha and Xiaoran Han and Smith, {Matthew D.} and Yang Liu and Gigu{\`e}re, {Patrick M.} and Dragana Kopanja and Pradip Raychaudhuri and Siderovski, {David P.} and Guan, {Kun Liang} and Lei, {Qun Ying} and Yue Xiong",

note = "Funding Information: We thank the members of the Fudan MCB and Xiong laboratories for discussions throughout this study; Brenda Temple of UNC R. L. Juliano Structural Bioinformatics Core facility for the molecular modeling; Bev Koller, Howard Rockman, Dennis Abraham, Kathleen Caron, and John Sondek for discussions; and Cam Patterson for discussion and critical reading of the paper. This work was supported by Chinese Ministry of Sciences and Technology 973 (grant no. 2015CB910401 and 2011CB910600), NSFC (grant no. 31271454, 81225016, and 81430057), Shanghai Key basic research program (12JC1401100), Shanghai Outstanding Academic Leader (Grant No.13XD1400600), and the Youth Science and Technology Leading Talent by MOST to Q.-Y.L.; NIH grants EY022611 and CA132809 (to K.-L.G.); and GM067113 (to Y.X.). Publisher Copyright: {\textcopyright} 2015 Elsevier Inc.",

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doi = "10.1016/j.molcel.2015.04.017",

language = "English",

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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

N1 - Funding Information: We thank the members of the Fudan MCB and Xiong laboratories for discussions throughout this study; Brenda Temple of UNC R. L. Juliano Structural Bioinformatics Core facility for the molecular modeling; Bev Koller, Howard Rockman, Dennis Abraham, Kathleen Caron, and John Sondek for discussions; and Cam Patterson for discussion and critical reading of the paper. This work was supported by Chinese Ministry of Sciences and Technology 973 (grant no. 2015CB910401 and 2011CB910600), NSFC (grant no. 31271454, 81225016, and 81430057), Shanghai Key basic research program (12JC1401100), Shanghai Outstanding Academic Leader (Grant No.13XD1400600), and the Youth Science and Technology Leading Talent by MOST to Q.-Y.L.; NIH grants EY022611 and CA132809 (to K.-L.G.); and GM067113 (to Y.X.). Publisher Copyright: © 2015 Elsevier Inc.

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.

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DO - 10.1016/j.molcel.2015.04.017

M3 - Article

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AN - SCOPUS:84931091401

VL - 58

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JO - Molecular Cell

JF - Molecular Cell

SN - 1097-2765

IS - 5

ER -

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

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