SUMOylation of Smad2 mediates TGF-β-regulated endothelial-mesenchymal transition

Qi Su; Xu Chen; Xing Ling; Danqing Li; Xiang Ren; Yang Zhao; Yanyan Yang; Yuhang Liu; Anqi He; Xinjie Zhu; Xinyi Yang; Wenbin Lu; Hongmei Wu; Yitao Qi

doi:10.1016/j.jbc.2023.105244

SUMOylation of Smad2 mediates TGF-β-regulated endothelial-mesenchymal transition

J Biol Chem. 2023 Oct;299(10):105244. doi: 10.1016/j.jbc.2023.105244. Epub 2023 Sep 9.

Authors

Qi Su¹, Xu Chen¹, Xing Ling¹, Danqing Li¹, Xiang Ren¹, Yang Zhao¹, Yanyan Yang¹, Yuhang Liu¹, Anqi He¹, Xinjie Zhu¹, Xinyi Yang¹, Wenbin Lu¹, Hongmei Wu², Yitao Qi³

Affiliations

¹ Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Developing of Endangered Chinese Crude Drugs in Northwest China, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, China.
² Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Developing of Endangered Chinese Crude Drugs in Northwest China, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, China. Electronic address: hq8479@snnu.edu.cn.
³ Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Developing of Endangered Chinese Crude Drugs in Northwest China, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, China. Electronic address: qiyitao@snnu.edu.cn.

Abstract

Endothelial-mesenchymal transition (EndoMT) is a complex biological process in which endothelial cells are transformed into mesenchymal cells, and dysregulated EndoMT causes a variety of pathological processes. Transforming growth factor beta (TGF-β) signaling effectively induces the EndoMT process in endothelial cells, and Smad2 is the critical protein of the TGF-β signaling pathway. However, whether small ubiquitin-like modifier modification (SUMOylation) is involved in EndoMT remains unclear. Here, we show that Smad2 is predominantly modified by SUMO1 at two major SUMOylation sites with PIAS2α as the primary E3 ligase, whereas SENP1 (sentrin/SUMO-specific protease 1) mediates the deSUMOylation of Smad2. In addition, we identified that SUMOylation significantly enhances the transcriptional activity and protein stability of Smad2, regulating the expression of downstream target genes. SUMOylation increases the phosphorylation of Smad2 and the formation of the Smad2-Smad4 complex, thus promoting the nuclear translocation of Smad2. Ultimately, the wildtype, but not SUMOylation site mutant Smad2 facilitated the EndoMT process. More importantly, TGF-β enhances the nuclear translocation of Smad2 by enhancing its SUMOylation and promoting the EndoMT process. These results demonstrate that SUMOylation of Smad2 plays a critical role in the TGF-β-mediated EndoMT process, providing a new theoretical basis for the treatment and potential drug targets of EndoMT-related clinical diseases.

Keywords: EndoMT; SENP1; SUMOylation; TGF-β; smad2.