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Overexpression of ubiquitin-specific peptidase 15 in systemic sclerosis fibroblasts increases response to transforming growth factor β. | LitMetric

AI Article Synopsis

  • - The study investigates the role of ubiquitin-specific peptidases (USPs) in systemic sclerosis (SSc), identifying that their expression is increased in SSc tenosynovial and skin samples, which impacts cell metabolism and signaling pathways like TGF-β.
  • - Researchers utilized transcriptomic studies and immunostaining to analyze USPs' presence and confirmed that TGF-β stimulation raises USP expression in fibroblast cell lines.
  • - Findings indicate that inhibiting USPs can reduce TGF-β signaling-related fibrotic responses, suggesting USPs, particularly USP15, could be promising therapeutic targets for treating SSc.

Article Abstract

Objective: Ubiquitination of proteins leads to their degradation by the proteasome, and is regulated by ubiquitin ligases and substrate-specific ubiquitin-specific peptidases (USPs). The ubiquitination process also plays important roles in the regulation of cell metabolism and cell cycle. Here, we found that the expression of several USPs is increased in SSc tenosynovial and skin biopsies, and we demonstrated that USP inhibition decreases TGF-β signalling in primary fibroblast cell lines.

Methods: High-density transcriptomic studies were performed using total RNA obtained from SSc tenosynovial samples. Confirmatory immunostaining experiments were performed on tenosynovial and skin samples. In vitro experiments were conducted in order to study the influence of USP modulation on responses to TGF-β stimulation.

Results: Tenosynovial biopsies from SSc patients overexpressed known disease-associated gene pathways: fibrosis, cytokines and chemokines, and Wnt/TGF-β signalling, but also several USPs. Immunohistochemistry experiments confirmed the detection of USPs in the same samples, and in SSc skin biopsies. Exposure of primary fibroblast cell lines to TGF-β induced USP gene expression. The use of a pan-USP inhibitor decreased SMAD3 phosphorylation, and expression of COL1A1, COL3A1 and fibronectin gene expression in TGF-β-stimulated fibroblasts. The effect of the USP inhibitor resulted in increased SMAD3 ubiquitination, and was blocked by a proteasome inhibitor, thereby confirming the specificity of its action.

Conclusion: Overexpression of several USPs, including USP15, amplifies fibrotic responses induced by TGF-β, and is a potential therapeutic target in SSc.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6434377PMC
http://dx.doi.org/10.1093/rheumatology/key401DOI Listing

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