Photoaffinity labeling coupled with proteomics identify PDI-ADAM17 module is targeted by (?)-vinigrol to induce TNFR1 shedding and ameliorate rheumatoid arthritis in mice

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  • 作者:Yinhua Zhu, Lu Wang, Jing Li, Yuan Zhao, Xuerong Yu, Ping Liu, Xiaobing Deng, Jingjing Liu, Fan Yang, Yini Zhang, Jiaojiao Yu, Luhua Lai, Chu Wang, Zhanguo Li, Lei Wang, Tuoping Luo
  • 期刊:Cell Chemical Biology
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Various biological agents have been developed to target tumor necrosis factor alpha (TNF-a) and its receptor
TNFR1 for the rheumatoid arthritis (RA) treatment, whereas small molecules modulating such cytokine receptors are rarely reported in comparison to the biologicals. Here, by revealing the mechanism of action of vinigrol, a diterpenoid natural product, we show that inhibition of the protein disulfide isomerase (PDI, PDIA1) by
small molecules activates A disintegrin and metalloprotease 17 (ADAM17) and then leads to the TNFR1 shedding on mouse and human cell membranes. This small-molecule-induced receptor shedding not only effectively blocks the inflammatory response caused by TNF-a in cells, but also reduces the arthritic score and
joint damage in the collagen-induced arthritis mouse model. Our study indicates that targeting the PDIADAM17 signaling module to regulate the shedding of cytokine receptors by the chemical approach constitutes a promising strategy for alleviating RA.

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