Proinflammatory Effects of Ubiquitin-Specific Protease 5 (USP5) in Rheumatoid Arthritis Fibroblast-Like Synoviocytes

Abstract

Rheumatoid arthritis (RA) is a worldwide chronic autoimmune inflammatory disease which is affecting approximately 1% of the total population. It is characterized by abnormal proliferation of fibroblast-like synoviocytes (FLS) and increased production of proinflammatory cytokines. In the current study, we were aiming to investigate the role of ubiquitin-specific protease 5 (USP5) in the inflammatory process in RA-FLS. Expression of USP5 was found upregulated in RA-FLS compared with that in osteoarthritis- (OA-) FLS, and IL-1β stimulation increased USP5 expression in a time-dependent manner. Furthermore, we found that USP5 overexpression significantly aggravated proinflammatory cytokine production and related nuclear factor κB (NF-κB) signaling activation. Consistently, silencing of USP5 decreased the release of cytokines and inhibited the activation of NF-κB. In addition, USP5 was found to interact with tumor necrosis factor receptor-associated factor 6 (TRAF6) and remove its K48-linked polyubiquitination chains therefore stabilizing TRAF6. Our data showed that a USP5-positive cell regulates inflammatory processes in RA-FLS and suggested USP5 as a potential target for RA treatment.

Morin Acts as a USP7 Inhibitor to Hold Back the Migration of Rheumatoid Arthritis Fibroblast‐Like Synoviocytes in a “Prickle1‐mTORC2” Dependent Manner

“…[ 42 ] Of note, the expression of USP7 and USP5 is increased in the FLS of patients with RA or peripheral blood mononuclear cells of patients with systemic lupus erythaematosus. [ 43,44 ] Overexpression of USP7 promotes the invasion of human DU145, PC3, 293T, HeLa, and T98G cells. P22077, an inhibitor of USP7, prevents the migration of Huh7 and SK‐Hep1 cells.…”

Macrophage‐derived extracellular vesicles regulates USP5‐mediated HDAC2/NRF2 axis to ameliorate inflammatory pain

“…24,51 Our in vitro and in vivo experiments provided further evidence demonstrating that miR-23a-3p targets and downregulates the expression of USP5. Accumulating evidence has been presented suggesting the pro-inflammatory properties of USP5, [52][53][54] which led us to investigate whether USP5 plays a role with miR-23a-3p in the sensation of inflammatory pain. HDAC2 have been reported to be stabilized by USP family members, including USP5 in ovarian cancer.…”

Epigenetic Regulation in the Pathogenesis of Rheumatoid Arthritis

“…Ubiquitination is an essential protein post-translational modification mechanism whose main role includes protein degradation and its functional regulation. The expression of ubiquitin-specific protease 5 (USP5) is significantly upregulated upon stimulation with IL-1β which increases the USP5 levels in a time-dependent manner in RA-FLS ( 37 ). Overexpression of USP5 significantly stimulates the production of pro-inflammatory cytokines and activation of the related nuclear factor kappa B (NF-κB) signaling pathway.…”