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Oxidative stress promotes fibrosis in systemic sclerosis through stabilization of a kinase-phosphatase complex
Ruiyuan Zhang, … , Wolfgang Peti, Nunzio Bottini
Ruiyuan Zhang, … , Wolfgang Peti, Nunzio Bottini
Published April 22, 2022
Citation Information: JCI Insight. 2022;7(8):e155761. https://doi.org/10.1172/jci.insight.155761.
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Research Article Inflammation

Oxidative stress promotes fibrosis in systemic sclerosis through stabilization of a kinase-phosphatase complex

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Abstract

Systemic sclerosis (SSc) is a fibrotic autoimmune disease characterized by pathogenic activation of fibroblasts enhanced by local oxidative stress. The tyrosine phosphatase PTP4A1 was identified as a critical promoter of TGF-β signaling in SSc. Oxidative stress is known to functionally inactivate tyrosine phosphatases. Here, we assessed whether oxidation of PTP4A1 modulates its profibrotic action and found that PTP4A1 forms a complex with the kinase SRC in scleroderma fibroblasts, but surprisingly, oxidative stress enhanced rather than reduced PTP4A1’s association with SRC and its profibrotic action. Through structural assessment of the oxo-PTP4A1-SRC complex, we unraveled an unexpected mechanism whereby oxidation of a tyrosine phosphatase promotes its function through modification of its protein complex. Considering the importance of oxidative stress in the pathogenesis of SSc and fibrosis, our findings suggest routes for leveraging PTP4A1 oxidation as a potential strategy for developing antifibrotic agents.

Authors

Ruiyuan Zhang, Ganesan Senthil Kumar, Uwe Hansen, Martina Zoccheddu, Cristiano Sacchetti, Zachary J. Holmes, Megan C. Lee, Denise Beckmann, Yutao Wen, Zbigniew Mikulski, Shen Yang, Eugenio Santelli, Rebecca Page, Francesco Boin, Wolfgang Peti, Nunzio Bottini

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Figure 5

SRC binds PTP4A1 through its SH3 and SH2 domains.

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SRC binds PTP4A1 through its SH3 and SH2 domains.
(A) Two-dimensional [1...
(A) Two-dimensional [1H,15N] TROSY spectra of SRC SH3SH2 in the absence (black) or presence of excess oxidized (red) and reduced (magenta) PTP4A1. (B) Diagram of CSP of SRC SH3SH2 upon binding of oxidized (left) and reduced (right) PTP4A1 as in Figure 4A and mapping of residues showing chemical shift changes (blue) and reduced intensity (magenta; I/I0 < 0.7) onto the structure of SRC SH3SH2 (PDB ID 2SRC) for (C) oxidized and (D) reduced PTP4A1. The key interacting regions of SRC SH2SH3 are labeled.

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