Auranofin targets UBA1 and enhances UBA1 activity by facilitating ubiquitin trans-thioesterification to E2 ubiquitin-conjugating enzymes.
Auranofin targets UBA1 and enhances UBA1 activity by facilitating ubiquitin trans-thioesterification to E2 ubiquitin-conjugating enzymes.
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DOI：
10.1038/s41467-023-40537-x
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发表时间：
2023-08-09
影响因子：
16.6
通讯作者：
Fang, Shengyun
中科院分区：
文献类型：
--
作者：
Yan, Wenjing;Zhong, Yongwang;Hu, Xin;Xu, Tuan;Zhang, Yinghua;Kales, Stephen;Qu, Yanyan;Talley, Daniel C. C.;Baljinnyam, Bolormaa;LeClair, Christopher A. A.;Simeonov, Anton;Polster, Brian M. M.;Huang, Ruili;Ye, Yihong;Rai, Ganesha;Henderson, Mark J. J.;Tao, Dingyin;Fang, Shengyun
UBA 1是主要的E1泛素活化酶，负责产生泛素化所需的活化泛素，这是一个调节许多蛋白质稳定性和功能的过程。泛素化减少或不足会导致或驱动衰老和许多疾病。因此，增强UBA 1活性的小分子可能具有广泛的治疗潜力。在这里，我们报告说，金诺芬，一种被批准用于治疗类风湿性关节炎的药物，是一种有效的UBA 1活性增强剂。金诺芬与UBA 1的泛素折叠结构域结合并与Cys1039残基缀合。这种结合增强了UBA 1与至少20种不同的E2泛素结合酶的相互作用，促进了泛素向E2充电，并增加了7种代表性E3的体外活性。在低纳摩尔浓度下，金诺芬在细胞中ER相关降解期间促进错误折叠的ER蛋白的泛素化和降解。它还促进线粒体外膜相关降解。这些发现表明，金诺芬可以作为UBA 1研究和治疗探索的急需工具。E1泛素激活酶UBA1的活性降低会导致衰老和阿尔茨海默氏症和VEXAS综合征等疾病。在这里，作者发现金诺芬，一种类风湿性关节炎药物，可以显着提高UBA 1活性。
UBA1 is the primary E1 ubiquitin-activating enzyme responsible for generation of activated ubiquitin required for ubiquitination, a process that regulates stability and function of numerous proteins. Decreased or insufficient ubiquitination can cause or drive aging and many diseases. Therefore, a small-molecule enhancing UBA1 activity could have broad therapeutic potential. Here we report that auranofin, a drug approved for the treatment of rheumatoid arthritis, is a potent UBA1 activity enhancer. Auranofin binds to the UBA1’s ubiquitin fold domain and conjugates to Cys1039 residue. The binding enhances UBA1 interactions with at least 20 different E2 ubiquitin-conjugating enzymes, facilitating ubiquitin charging to E2 and increasing the activities of seven representative E3s in vitro. Auranofin promotes ubiquitination and degradation of misfolded ER proteins during ER-associated degradation in cells at low nanomolar concentrations. It also facilitates outer mitochondrial membrane-associated degradation. These findings suggest that auranofin can serve as a much-needed tool for UBA1 research and therapeutic exploration. Decreased activity of the E1 ubiquitin-activating enzyme UBA1 can contribute to aging and diseases like Alzheimer’s and VEXAS syndrome. Here, the authors found that auranofin, a rheumatoid arthritis drug, can significantly boost UBA1 activity.
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影响因子：
16.6
作者：
通讯作者：
--
影响因子：
82.9
作者：
Hyer, Marc L.;Milhollen, Michael A.;Bence, Neil F.
通讯作者：
Bence, Neil F.
影响因子：
11.4
作者：
Das, Ranabir;Liang, Yu-He;Byrd, R. Andrew
通讯作者：
Byrd, R. Andrew
影响因子：
11.2
作者：
Hooda, Jagmohan;Novak, Marian;Drapkin, Ronny
通讯作者：
Drapkin, Ronny
健康衰老和疾病中的自噬。
DOI：
10.1038/s43587-021-00098-4
发表时间：
2021-08
期刊：
Nature aging
影响因子：
--
作者：
Aman Y;Schmauck-Medina T;Hansen M;Morimoto RI;Simon AK;Bjedov I;Palikaras K;Simonsen A;Johansen T;Tavernarakis N;Rubinsztein DC;Partridge L;Kroemer G;Labbadia J;Fang EF
通讯作者：
Fang EF