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

Acta Pharmaceutica Sinica B 2024年第3期14卷 1222-1240页

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 Institute of Clinical Pharmacology Anhui Medical UniversityKey Laboratory of Anti-inflammatory and Immune MedicineMinistry of EducationCollaborative Innovation Center of Anti-inflammatory and Immune MedicinesHefei 230032China School of Pharmacy Bengbu Medical CollegeBengbu 233030China The Third Affiliated Hospital of Anhui Medical University(the First People’s Hospital of Hefei) Hefei 230061China

Hyperplasia and migration of fibroblast-like synoviocytes(FLSs)are the key drivers in the pathogenesis of rheumatoid arthritis(RA)and joint *** 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 *** 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 ***,SAV1 protein expression is extremely ***,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 *** process further contributes to the decreased phosphorylation,nuclear translocation,and transcriptional potency of YAP,and leads to aberrant FLSs *** depletion of GRK2 or inhibition of GRK2 by paroxetine rescued SAV1 expression and restored YAP phosphorylation and finally inhibited RA FLSs proliferation and ***,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 ***,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

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