Celastrol Targets Cullin-Associated and Neddylation-Dissociated 1 to Prevent Fibroblast-Myofibroblast Transformation against Pulmonary Fibrosis.
Celastrol Targets Cullin-Associated and Neddylation-Dissociated 1 to Prevent Fibroblast-Myofibroblast Transformation against Pulmonary Fibrosis.
复制标题
DOI：
10.1021/acschembio.2c00099
复制
发表时间：
2022-09
影响因子：
4
通讯作者：
Yu Zhou-;Manru Li;Tao Shen;Tianming Yang;Gaona Shi;Yazi Wei;Chengjuan Chen;Dongmei Wang;Yanan Wang
中科院分区：
文献类型：
--
作者：
Yu Zhou-;Manru Li;Tao Shen;Tianming Yang;Gaona Shi;Yazi Wei;Chengjuan Chen;Dongmei Wang;Yanan Wang
南蛇藤酚（CEL）是一种五环三萜类化合物，具有明确的抗肺纤维化作用。然而，其抗肺纤维化的直接靶点仍然未知。在这项研究中，我们设计和合成了一系列雷公藤红素为基础的探针，以确定直接目标在人肺成纤维细胞使用活性为基础的蛋白质谱分析策略。在众多被钓取的靶点中，我们发现了一个关键蛋白，cullin相关和neddylation-dissociated 1（CAND 1），它参与成纤维细胞-肌成纤维细胞转化（FMT）。更重要的是，我们发现雷公藤红素对FMT的抑制作用依赖于CAND 1，通过改善CAND 1和Cullin 1之间的相互作用，促进Skp 1/Cullin 1/F-box泛素连接酶的活性。计算机模拟研究和半胱氨酸突变实验进一步证明CAND 1的Cys 264是雷公藤红素的缀合位点。这揭示了雷公藤红素抗肺纤维化的新机制，可能为抗肺纤维化提供新的治疗选择。
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.