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OBJECTIVES: Autophagy is a homeostatic and physiological process that promotes the turnover of proteins and organelles damaged in conditions of cellular stress. We previously demonstrated that autophagy represents a key processing event creating a substrate for autoreactivity, which is involved in post-translational changes and generation of citrullinated peptides, recognized by the immune system in RA. In this study, we analysed whether autophagy is involved in other post-translational changes that can generate autoantigens, focusing on carbamylation processes. Carbamylation is a nonenzymatic post-translational modification, in which homocitrulline is generated by the reaction of cyanate with the primary amine of lysine residues; carbamylated peptides may accumulate during inflammation conditions. METHODS: The role of autophagy in the generation of carbamylated proteins was evaluated in vitro in fibroblasts as well as in synoviocytes from RA patients, treated with 5 μM tunicamycin or 200 nM rapamycin; the correlation between autophagy and carbamylated proteins was analysed in mononuclear cells from 30 naïve early-active RA patients. RESULTS: Our results demonstrated that cells treated with tunicamycin or rapamycin showed a significant increase of carbamylated proteins. Immunoblotting and immunoprecipitation experiments identified vimentin as the main carbamylated protein. Furthermore, a correlation was found between autophagy and carbamylation levels in mononuclear cells of naïve RA patients. CONCLUSION: These data indicate that autophagy is able to induce in vitro carbamylation processes, and in vivo appears to be related to an increase in carbamylation during RA. These observations introduce a new pathogenetic mechanism of disease, which could contribute to more accurate monitoring of patients.

Autophagy induces protein carbamylation in fibroblast-like synoviocytes from patients with rheumatoid arthritis / Manganelli, Valeria; Recalchi, Serena; Capozzi, Antonella; Riitano, Gloria; Mattei, Vincenzo; Longo, Agostina; Di Franco, Manuela; Alessandri, Cristiano; Bombardieri, Michele; Valesini, Guido; Misasi, Roberta; Garofalo, Tina; Sorice, Maurizio. - In: RHEUMATOLOGY. - ISSN 1462-0324. - ELETTRONICO. - (2018).

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