Zhao Kailiang, Hu Hao, Fang Debao, Xie Mingran, Chen Jiasheng, Zhang Shan, Tang Suyun, Wu Mingsheng, Guo Xiaorui, Yu Ning, Yao Bao, Jiang Wenli, Wang Chao, Mei Yide
Department of Thoracic Surgery, The First Affiliated Hospital of USTC, National Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
Nat Struct Mol Biol. 2025 May 26. doi: 10.1038/s41594-025-01576-8.
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.
泛素样修饰因子（“UFMylation”）修饰在调节转移过程中的作用一直不明确。细胞迁移是转移过程中的关键步骤，由片状伪足前沿的肌动蛋白相关蛋白2和3（Arp2/3）介导的肌动蛋白聚合驱动。在此，我们报道UFM1特异性E3连接酶1（UFL1）与Arp2/3复合物的核心亚基ArpC4相互作用并催化其UFMylation。Akt在此过程中起关键作用，这涉及在T426位点磷酸化UFL1，从而增强其与ArpC4的相互作用并诱导ArpC4的UFMylation。通过ArpC4的UFMylation以及潜在的其他靶点，UFL1促进片状伪足形成并促进细胞迁移、侵袭和转移，使UFL1成为有吸引力的癌症治疗靶点。
