Ubiquitin specific peptidase 13 protects against inflammation-associated joint injury in collagen-induced rheumatoid arthritis mice by targeting TRAF6.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease with complex pathogenesis. Ubiquitin-specific protease 13 (USP13), a member of the deubiquitinating enzyme (DUB) superfamily, plays diverse roles in cellular events. This study investigates the role of USP13 in RA, revealing its significant downregulation in peripheral blood mononuclear cells (PBMCs) from RA patients compared to healthy individuals. USP13 expression negatively correlates with RA characteristics, including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and rheumatoid factor (RF). Consistent with these findings, USP13 levels were reduced in knee joint synovial tissues of collagen-induced arthritis (CIA) mice and lipopolysaccharide (LPS)-stimulated bone marrow-derived macrophages (BMDMs). Mechanistically, USP13 directly interacts with tumor necrosis factor receptor-associated factor 6 (TRAF6), reducing its K63-linked polyubiquitination and thereby inhibiting TRAF6 expression. This interaction restrains nuclear factor κB (NF-κB) signaling, leading to a marked attenuation of LPS-induced inflammatory responses in BMDMs. Importantly, the anti-inflammatory effects of USP13 over-expression are largely dependent on TRAF6 suppression. In vitro, USP13 over-expression in BMDMs inhibits the proliferation of fibroblast-like synoviocytes (FLS) and osteoclastogenesis. In addition, USP13-overexpressing BMDMs in CIA mice significantly alleviates RA development, as evidenced by reduced synovial hyperplasia, inflammatory cell infiltration, cartilage destruction, and bone loss. These findings highlight the essential role of USP13 in macrophages during RA progression and reveal its therapeutic potential by targeting TRAF6 signaling.