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The Ubiquitin Proteasome System and Skin Fibrosis

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Abstract

The ubiquitin proteasome system (UPS) is a highly conserved way to regulate protein turnover in cells. The UPS hydrolyzes and destroys variant or misfolded proteins and finely regulates proteins involved in differentiation, apoptosis, and other biological processes. This system is a key regulatory factor in the proliferation, differentiation, and collagen secretion of skin fibroblasts. E3 ubiquitin protein ligases Parkin and NEDD4 regulate multiple signaling pathways in keloid. Tumor necrosis factor (TNF) receptor-associated factor 4 (TRAF4) binding with deubiquitinase USP10 can induce p53 destabilization and promote keloid-derived fibroblast proliferation. The UPS participates in the occurrence and development of hypertrophic scars by regulating the transforming growth factor (TGF)-β/Smad signaling pathway. An initial study suggests that TNFα-induced protein 3 (TNFAIP3) polymorphisms may be significantly associated with scleroderma susceptibility in individuals of Caucasian descent. Sumoylation and multiple ubiquitin ligases, including Smurfs, UFD2, and KLHL42, play vital roles in scleroderma by targeting the TGF-β/Smad signaling pathway. In the future, drugs targeting E3 ligases and deubiquitinating enzymes have great potential for the treatment of skin fibrosis.

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  1. Wanlu Shen, Zhigang Zhang and Jiaqing Ma contributed equally to this work and should be considered joint first authors.

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  1. Science and Technology Achievement Incubation Center, Kunming Medical University, 1168 West Chunrong Road, Yuhua Avenue, Chenggong District, Kunming, 650500, Yunnan, China

    Wanlu Shen, Zhigang Zhang, Di Lu & Lechun Lyu

  2. School of Basic Medical Sciences, Kunming Medical University, Kunming, China

    Jiaqing Ma

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This work was supported by grants from the National Natural Science Foundation of China (NSFC; grant no. 81560502, 81960354), the Talent Project of Yunnan Province (2019HB024), the National Natural Science Foundation of Yunnan Province (grant no. 2019FE001-184), and the 100 Talents Program of Kunming Medical University (Lechun Lyu).

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Wanlu Shen, Zhigang Zhang, Jiaqing Ma, Di Lu, and Lechun Lyu have no conflicts of interest that are directly relevant to the content of this article.

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Lechun Lyu and Di Lu contributed to the study conception and design. Wanlu Shen, Zhigang Zhang, Jiaqing Ma, Lechun Lyu and Di Lu prepared the main manuscript; All authors have read and approved the final article.

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Shen, W., Zhang, Z., Ma, J. et al. The Ubiquitin Proteasome System and Skin Fibrosis. Mol Diagn Ther 25, 29–40 (2021). https://doi.org/10.1007/s40291-020-00509-z

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