雷公藤醇
肺纤维化
癌症研究
肌成纤维细胞
接合作用
纤维化
细胞生物学
特发性肺纤维化
心脏纤维化
生物
泛素
化学
肺
医学
生物化学
泛素连接酶
病理
内科学
细胞凋亡
基因
作者
Yu Zhang,Manru Li,Tao Shen,Tao Yang,Gaona Shi,Yazi Wei,Chengjuan Chen,Dongmei Wang,Ya-Nan Wang,Tiantai Zhang
标识
DOI:10.1021/acschembio.2c00099
摘要
Celastrol (CEL), a pentacyclic triterpene compound, has been proven to have a definite antipulmonary fibrosis effect. However, its direct targets for antipulmonary fibrosis remain unknown. In this study, we designed and synthesized a series of celastrol-based probes to identify the direct targets in human pulmonary fibroblasts using an activity-based protein profiling strategy. Among many fished targets, we identified a key protein, cullin-associated and neddylation-dissociated 1 (CAND1), which was involved in fibroblast–myofibroblast transformation (FMT). More importantly, we found that the inhibitory effect of celastrol on FMT is dependent on CAND1, through improving the interactions between CAND1 and Cullin1 to promote the activity of Skp1/Cullin1/F-box ubiquitin ligases. In silico studies and cysteine mutation experiments further demonstrated that Cys264 of CAND1 is the site for conjugation of celastrol. This reveals a new mechanism of celastrol against pulmonary fibrosis and may provide a novel therapeutic option for antipulmonary fibrosis.
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