Kailiang Zhao, Hao Hu, Debao Fang, Mingran Xie, Jiasheng Chen, Shan Zhang, Suyun Tang, Mingsheng Wu, Xiaorui Guo, Ning Yu, Bao Yao, Wenli Jiang, Chao Wang, Yide Mei
{"title":"Akt-phosphorylated UFL1 UFMylates ArpC4 to promote metastasis","authors":"Kailiang Zhao, Hao Hu, Debao Fang, Mingran Xie, Jiasheng Chen, Shan Zhang, Suyun Tang, Mingsheng Wu, Xiaorui Guo, Ning Yu, Bao Yao, Wenli Jiang, Chao Wang, Yide Mei","doi":"10.1038/s41594-025-01576-8","DOIUrl":null,"url":null,"abstract":"<p>The role of modification by ubiquitin-fold modifier (‘UFMylation’) in regulating metastasis has remained enigmatic. Cell migration, a critical step in metastasis, is driven by actin polymerization mediated by actin-related proteins 2 and 3 (Arp2/3) at the leading edge of lamellipodia. Here, we report that UFM1-specific E3 ligase 1 (UFL1) interacts with and catalyzes the UFMylation of ArpC4, a core subunit of the Arp2/3 complex. Akt has a key role in this process, which involves phosphorylating UFL1 at T426, thereby enhancing its interaction with ArpC4 and inducing ArpC4 UFMylation. Through ArpC4 UFMylation and potentially other targets, UFL1 facilitates lamellipodia formation and promotes cell migration, invasion and metastasis, making UFL1 an attractive therapeutic target for cancer.</p>","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"24 1","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature structural & molecular biology","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1038/s41594-025-01576-8","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
Abstract
The role of modification by ubiquitin-fold modifier (‘UFMylation’) in regulating metastasis has remained enigmatic. Cell migration, a critical step in metastasis, is driven by actin polymerization mediated by actin-related proteins 2 and 3 (Arp2/3) at the leading edge of lamellipodia. Here, we report that UFM1-specific E3 ligase 1 (UFL1) interacts with and catalyzes the UFMylation of ArpC4, a core subunit of the Arp2/3 complex. Akt has a key role in this process, which involves phosphorylating UFL1 at T426, thereby enhancing its interaction with ArpC4 and inducing ArpC4 UFMylation. Through ArpC4 UFMylation and potentially other targets, UFL1 facilitates lamellipodia formation and promotes cell migration, invasion and metastasis, making UFL1 an attractive therapeutic target for cancer.
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