Synoviolin, protein folding and the maintenance of joint homeostasis

Rheumatoid arthritis is a disease associated with painful joints that affects approximately 1% of the population worldwide, and for which no specific cure is available. Among other functions, the endoplasmic reticulum (ER) has an important role in protein folding. When the level of unfolded proteins in the ER exceeds the folding capacity of this organelle, defective proteins are eliminated by ER-associated degradation (ERAD), an ATP-dependent ubiquitin-proteasome degradation process, to reduce the burden on the ER. Synoviolin is an E3 ubiquitin ligase that is involved in ERAD. This protein is a pathogenic factor for arthropathy; it is overexpressed in the synovial cells of patients with rheumatoid arthritis. This overexpression results in a 'hyper-ERAD' state, in which the cell deals with accumulated unfolded proteins excessively. Rheumatoid synovial cells produce large amounts of various proteins such as cytokines and proteases, which consequently might confer an autonomous proliferation property on the cells. At least 30% of all newly synthesized, ER-sorted proteins are unfolded. Although degradation of unfolded proteins consumes large amounts of ATP and would seem an unconventional process, it is essential for joint homeostasis.