METTL1-mediated internal m⁷G methylation of cathepsin B mRNA promotes synovial aggression in rheumatoid arthritis.

Abstract

Recent studies show that methyltransferase-like 1 (METTL1)-mediated internal messenger ribonucleic acid (mRNA) N⁷-methylguanosine (m⁷G) modification has a unique role in cancer metastasis. Here, we aimed to uncover the role of METTL1-mediated internal mRNA m⁷G in controlling fibroblast-like synoviocytes' (FLSs') functions in rheumatoid arthritis (RA). FLSs were separated from patients with active established RA. Western blot, immunohistochemistry, and immunofluorescence were used to measure protein expression in synovium. The Boyden chamber was used to detect cell migration and invasion. m⁷G RNA immunoprecipitation sequencing was performed to seek the potential target of METTL1. Dual-luciferase reporter gene assay was used to investigate the m⁷G-dependent regulation of cathepsin B (CTSB) by METTL1. The protein translation efficiency was detected by polysome profiling. METTL1 heterozygous knockout or intra-articular injection of METTL1 short hairpin ribonucleic acid adenovirus (Adv-shRNA-METTL1) was used to inhibit arthritis in RA models. We observed increased levels of METTL1 and internal mRNA m⁷G in FLSs and synovial tissues from patients with RA. METTL1 knockdown or overexpression decreased or increased the migration and invasion of RA FLSs. Synovial METTL1 level was positively correlated with the disease activity score on 28 joints-erythrocyte sedimentation rate scores in patients with RA. METTL1 knockdown in vivo mitigated the severity of arthritis in RA animal models. Mechanistically, we probed that METTL1 promotes the aggressive action of RA FLSs through regulating the translation efficiency of the internal mRNA m⁷G modification of CTSB. CTSB knockdown also suppressed the aggression of RA FLSs. Our findings reveal an important role of METTL1-mediated internal mRNA m⁷G modification in promoting synovial aggression of RA, suggesting that METTL1 might be a potential target for therapy of RA, even other dysregulated FLS-associated diseases.