GRK2 activates TRAF2-NF-κB signalling to promote hyperproliferation of fibroblast-like synoviocytes in rheumatoid arthritis.
10.1016/j.apsb.2025.02.031
- Author:
Chenchen HAN
1
;
Liping JIANG
1
;
Weikang WANG
1
;
Shujun ZUO
1
;
Jintao GU
1
;
Luying CHEN
1
;
Zhuo CHEN
1
;
Jiajie KUAI
1
;
Xuezhi YANG
1
;
Liang XU
2
;
Yang MA
1
;
Wei WEI
1
Author Information
1. Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei 230032, China.
2. Orthopedic Department, First Affiliated Hospital of the University of Science and Technology of China (USTC), Anhui Provincial Hospital, Hefei 230002, China.
- Publication Type:Journal Article
- Keywords:
Fibroblast-like synoviocytes;
G protein-coupled receptor kinase 2;
Hyperproliferation;
Rheumatoid arthritis;
Tumor necrosis factor receptor-associated factor 2
- From:
Acta Pharmaceutica Sinica B
2025;15(4):1956-1973
- CountryChina
- Language:English
-
Abstract:
G protein-coupled receptor kinase 2 (GRK2) participates in the phosphorylation and desensitization of G protein-coupled receptor (GPCR), impacting various biological processes such as inflammation and cell proliferation. Dysregulated expression and activity of GRK2 have been reported in multiple cells in rheumatoid arthritis (RA). However, whether and how GRK2 regulates synovial hyperplasia and fibroblast-like synoviocytes (FLSs) proliferation is poorly understood. In this study, we investigated the regulation of GRK2 and its biological function in RA. We found that GRK2 transmembrane activity was increased in FLSs of RA patients and collagen-induced arthritis (CIA) rats. Additionally, we noted a positive correlation between high GRK2 expression on the cell membrane and serological markers associated with RA and CIA. Immunoprecipitation-mass spectrometry and pull-down analyses revealed tumor necrosis factor receptor-associated factor 2 (TRAF2) as a novel substrate of GRK2. Furthermore, surface plasmon resonance (SPR) and molecular docking assays determined that the C-terminus of GRK2 binds to the C-terminus of TRAF2 at the Gln340 residue. GRK2 knockdown and the GRK2 inhibitor CP-25 attenuated synovial hyperplasia and FLS proliferation in CIA both in vitro and in vivo by decreasing GRK2 membrane expression and activity. Mechanistically, increased GRK2 transmembrane activity contributed to the recruitment of TRAF2 on the cell membrane, promoting GRK2-TRAF2 interactions that facilitate the recruitment of the E3 ubiquitin ligase TRIM47 to TRAF2. This enhanced TRAF2 Lys63 polyubiquitylation and induced nuclear factor (NF)-κB activation, leading to synovial hyperplasia and abnormal proliferation of FLSs. Our study provides a mechanistic and preclinical rationale for further evaluation of GRK2 as a therapeutic target for RA.
