GRK2 mediated degradation of SAV1 initiates hyperplasia of fibroblast-like synoviocytes in rheumatoid arthritis  

作　　者：Paipai Guo Ji Jiang Rui Chu Feng He Mingli Ge Ruhong Fang Qiuyun Guan Huijuan Cheng Chunru Jiang Tiantian Su Zhenduo Zhu Hao Liu Wei Wei Shihao Zhang Qingtong Wang 

机构地区：[1]Institute of Clinical Pharmacology,Anhui Medical University,Key Laboratory of Anti-inflammatory and Immune Medicine,Ministry of Education,Collaborative Innovation Center of Anti-inflammatory and Immune Medicines,Hefei 230032,China [2]School of Pharmacy,Bengbu Medical College,Bengbu 233030,China [3]The Third Affiliated Hospital of Anhui Medical University(the First People’s Hospital of Hefei),Hefei 230061,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第3期1222-1240,共19页药学学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(81973314,82373865,81973332,82173824);the Anhui Provincial Natural Science Foundation for Distinguished Young Scholars(1808085J28,China);Collaborative Innovation Project of Key Scientific Research Platform in Anhui Universities(GXXT-2020-066,China);the Research Program for Higher Education Institutions in Anhui Province(2022AH030081,China);Anhui Provincial Key R&D Programs(2022e07020042,China);Program for Upgrading Scientific Research Level of Anhui Medical University(2019xkj T008,China);Academic Funding for Top-notch Talents in University Disciplines(Majors)of Anhui Province(gxbj ZD2021047,China)。

摘　　要：Hyperplasia and migration of fibroblast-like synoviocytes(FLSs)are the key drivers in the pathogenesis of rheumatoid arthritis(RA)and joint destruction.Abundant Yes-associated protein(YAP),which is a powerful transcription co-activator for proliferative genes,was observed in the nucleus of inflammatory FLSs with unknown upstream mechanisms.Using Gene Expression Omnibus database analysis,it was found that Salvador homolog-1(SAV1),the pivotal negative regulator of the Hippo-YAP pathway,was slightly downregulated in RA synovium.However,SAV1 protein expression is extremely reduced.Subsequently,it was revealed that SAV1 is phosphorylated,ubiquitinated,and degraded by interacting with an important serine-threonine kinase,G protein-coupled receptor(GPCR)kinase 2(GRK2),which was predominately upregulated by GPCR activation induced by ligands such as prostaglandin E2(PGE2)in RA.This process further contributes to the decreased phosphorylation,nuclear translocation,and transcriptional potency of YAP,and leads to aberrant FLSs proliferation.Genetic depletion of GRK2 or inhibition of GRK2 by paroxetine rescued SAV1 expression and restored YAP phosphorylation and finally inhibited RA FLSs proliferation and migration.Similarly,paroxetine treatment effectively reduced the abnormal proliferation of FLSs in a rat model of collagen-induced arthritis which was accompanied by a significant improvement in clinical manifestations.Collectively,these results elucidate the significance of GRK2 regulation of Hippo-YAP signaling in FLSs proliferation and migration and the potential application of GRK2 inhibition in the treatment of FLSs-driven joint destruction in RA.

关 键 词：Rheumatoid arthritis Fibroblast-like synoviocytes G protein-coupled receptor kinase 2 Salvador homolog-1 Yes-associated protein 

分 类 号：R593.22[医药卫生—内科学]