title: Hypertension-associated C825T polymorphism impairs the function of Gβ3 to target GRK2 ubiquitination.
abstract: Population-based and case-control studies in different ethnicities have linked a polymorphism, C825T, in exon 10 of GNB3 gene to hypertension and several additional diseases. The 825T allele is associated with alternative splicing and results in a shortened Gβ3 protein, referred to as Gβ3s, which loses 41 amino acids encompassing one WD40 repeat domain. The mechanism of how Gβ3 C825T polymorphism is associated with hypertension has remained unclear, but an impairment of its canonical function in G-protein-coupled receptor signaling has been ruled out. Here, we report that Gβ3, like other Gβ proteins, binds to DDB1 and assembles a DDB1-CUL4A-ROC1 E3 ubiquitin ligase (CRL4A(Gβ3)) to target GRK2 ubiquitination. The loss of the 41 amino-acid residues disrupts the Gβ3-DDB1 binding and impairs the function of Gβ3s to ubiquitinate GRK2. GRK2 ubiquitination levels were decreased and protein levels were accumulated in the blood samples of Gβ3 825T allele carriers. Deletion of Cul4a in mice resulted in systolic pressure increased and weakened heart function in male mice that can be partially rescued by the deletion of one Grk2 allele. These results reveal a mechanism explaining the link between Gβ3 C825T polymorphism and hypertension.
authors.affiliation: Key Laboratory of Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, China; Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Fudan University, Shanghai, China; School of Life Sciences, Fudan University, Shanghai, China; Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Zhengyu
authors.initials: Z
authors.lastname: Zha
authors.affiliation: Key Laboratory of Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, China; Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Fudan University, Shanghai, China; School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: Xiao-Ran
authors.initials: XR
authors.lastname: Han
authors.affiliation: Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill , Chapel Hill, NC, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Smith
authors.affiliation: Key Laboratory of Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College , Shanghai, China.
authors.forename: Qun-Ying
authors.initials: QY
authors.lastname: Lei
authors.affiliation: Key Laboratory of Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, China; Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Fudan University, Shanghai, China; Department of Pharmacology and Moores Cancer Center, University of California at San Diego, La Jolla, CA, USA.
authors.forename: Kun-Liang
authors.initials: KL
authors.lastname: Guan
authors.affiliation: Key Laboratory of Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, China; Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Fudan University, Shanghai, China; Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Xiong