Abstract
Scleroderma (systemic sclerosis, SSc) is a highly heterogeneous rheumatic disease, and uncontrolled fibrosis in visceral organs is the major cause of death in patients. The transforming growth factor-β (TGF-β) and WNT/β-catenin signaling pathways, along with signal transducer and activator of transcription 3 (STAT3), play crucial roles in this fibrotic process. Currently, no therapy is available that effectively arrests or reverses the progression of fibrosis in patients with SSc. Ubiquitination is an important post-translational modification that controls many critical cellular functions. Dysregulated ubiquitination events have been observed in patients with systemic lupus erythematosus, rheumatoid arthritis and fibrotic diseases. Inhibitors targeting the ubiquitination pathway have considerable potential for the treatment of rheumatic diseases. However, very few studies have examined the role and mechanism of ubiquitination in patients with SSc. In this review, we will summarize the molecular mechanisms of ubiquitination in patients with SSc and explore the potential targets for treatment.
Highlights
Scleroderma is a complicated heterogeneous rheumatic disease that is characterized by progressive fibrosis in the skin and multiple other organs
In patients with SSc, the transforming growth factor-β (TGF-β) and WNT/β-catenin signaling pathways and signal transducer and activator of transcription 3 (STAT3) are mainly regulated by E3 ligases at multiple levels, which presents the potential for specific substrates for drug target design
Considering the central role of TGF-β signaling, WNT/β-catenin signaling and STAT3 in SSc, the use of ubiquitination-proteasome system (UPS) inhibitors to selectively disrupt the formation of receptor or co-receptor complexes or block intracellular signaling may yield advances in the development of urgently needed treatments
Summary
Reviewed by: Gianluca Moroncini, Università Politecnica delle Marche, Italy Luigi Racioppi, Università degli Studi di Napoli Federico II, Italy. Scleroderma (systemic sclerosis, SSc) is a highly heterogeneous rheumatic disease, and uncontrolled fibrosis in visceral organs is the major cause of death in patients. No therapy is available that effectively arrests or reverses the progression of fibrosis in patients with SSc. Ubiquitination is an important post-translational modification that controls many critical cellular functions. Dysregulated ubiquitination events have been observed in patients with systemic lupus erythematosus, rheumatoid arthritis and fibrotic diseases. Inhibitors targeting the ubiquitination pathway have considerable potential for the treatment of rheumatic diseases. Very few studies have examined the role and mechanism of ubiquitination in patients with SSc. In this review, we will summarize the molecular mechanisms of ubiquitination in patients with SSc and explore the potential targets for treatment
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