Dysregulated NUB1 and Neddylation Enhances Rheumatoid Arthritis Fibroblast-Like Synoviocyte Inflammatory Responses

Area of Science:

• Molecular Biology
• Immunology
• Rheumatology

Background:

• Fibroblast-like synoviocytes (FLS) drive rheumatoid arthritis (RA) pathogenesis via NF-κB activation.
• Neddylation, a post-translational modification, is regulated by NUB1 and influences cellular processes.

Purpose of the Study:

• To investigate if NUB1 and neddylation are dysregulated in RA FLS.
• To determine if these alterations contribute to the aggressive phenotype of RA FLS.

Main Methods:

• Gene and protein expression analysis (qPCR, Western blot) in RA and osteoarthritis (OA) FLS.
• NUB1 overexpression and IL-1β stimulation assays.
• Inhibition of neddylation (MLN4924) and proteasome assays.
• Assessment of arthritis severity in a K/BxN serum-transfer arthritis model.

Main Results:

• RA FLS showed altered NUB1 promoter histone modifications and reduced CUL1 neddylation compared to OA FLS.
• NUB1 overexpression and MLN4924 treatment decreased NF-κB activation and IL-6 production in RA FLS.
• MLN4924 treatment significantly reduced arthritis severity in the K/BxN mouse model.

Conclusions:

• Neddylation and NUB1 induction are dysregulated in RA FLS, promoting inflammation.
• Inhibition of neddylation demonstrates therapeutic potential in an arthritis model.
• Targeting the neddylation system offers a novel therapeutic strategy for RA.