N-homocysteinylation of β-arrestins biases GPCR signaling and promotes platelet activation
Abstract
Abstract Hyperhomocysteinemia (HHcy) is strongly associated with cardiovascular diseases (CVDs), and it has been identified as a risk factor for thrombotic diseases. Most patients with HHcy die from various complications closely related to thrombotic diseases. However, the underlying mechanisms have not been fully elucidated. G protein-coupled receptors (GPCRs), the central regulators of the cardiovascular system, primarily control platelet activation. By examining the effects of HHcy on a panel of GPCRs involved in platelet aggregation, we found that HHcy systematically modulated biased GPCR signaling through the inhibition of desensitization by β-arrestins and the amplification of G protein signals. We further revealed that the N-homocysteinylation of β-arrestin1/2 at lysine (K) residues (K294/K296) disrupted the interaction between β-arrestins and GPCRs. The aforementioned phenomenon may be universal because HHcy was found to modulate the signaling bias of 9 other randomly selected GPCRs. Moreover, we found that the proinflammatory effects of homocysteine and homocysteine thiolactone were weakened in Arrb2–/– mice and that the reintroduction of wild-type but not K296R β-arrestin2 mutants (in mice) into primary peritoneal macrophages reversed these effects. Notably, in Arrb2K296R mice, HHcy-induced thrombus formation and platelet aggregation were reversed. Our results suggest that a G-biased agonist could be a better choice for disease therapy under HHcy conditions. Collectively, our findings demonstrate that the N-homocysteinylation of β-arrestin1/β-arrestin2 actively modulates the biased property of GPCR signaling, which contributes to the pathophysiology of HHcy-related CVDs and provides insight into the selection of agonists for the treatment of diseases under HHcy conditions.
Article Details
Authors (20)
Lin-Qi Zhang
1Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China
Chang-Xiao Che
1Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China
Ya-Qin Du
1Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China
Lu-lu Han
School of Physics and Information Technology, Shaanxi Normal University 1 , Xi'an 710062,
Jia-Le Wang
State Key Laboratory of Physical Chemistry of Solid Surfaces, Key Laboratory of Chemical Biology of Fujian Province, College of Chemistry and Chemical Engineering
Chen-Yu Zhang
Shen-Ming Huang
1Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China
Zhong-Yuan Zheng
1Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China
Qing-Tao He
4Key Laboratory Experimental Teratology of the Ministry of Education and Department of Physiology, School of Basic Medical Sciences, Shandong University, Jinan, China
Zhao Yang
Beijing National Laboratory for Molecular Sciences, Key Laboratory of Organic Solids, Institute of Chemistry
Long Zhang
Nan Chen
National Engineering Research Center of Lower-Carbon Catalysis Technology, Dalian National Laboratory for Clean Energy, Dalian Institute of Chemical Physics
Fan Yang
Ying-Li Jia
1Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China
Shi-Min Zhao
9Obstetrics and Gynecology Hospital of Fudan University, State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China
De-Min Zhou
11State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
Chu Wang
Xian Wang
School of Chemistry and Materials Science
Jin-Peng Sun
Lu Tie
1Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China