西班牙生物科学合作研究中心Arkaitz Carracedo课题组揭示了多胺依赖性代谢屏蔽调节选择性剪接。相关论文发表在2026年1月14日出版的《自然》杂志上。

在这里，小组展示了多胺，对细胞内稳态至关重要的小聚合体，调节了mRNA前剪接的选择性过程。课题组人员发现多胺合成的抑制增加了剪接体蛋白的磷酸化，同时伴随着细胞和组织中选择性剪接的扰动。从机制上讲，分子模拟结合生化分析表明，多胺结合到U2小核核糖核蛋白SF3亚复合物剪接因子中的酸性磷酸化基序，从而阻止上游激酶的作用。小组将这种多胺调节蛋白质磷酸化的分子过程称为代谢屏蔽。

据悉，代谢物是细胞内稳态的核心。虽然很多人强调它们与满足能量和生物合成需求的相关性，但代谢中间体也起着信号分子的作用。

附：英文原文

Title: Polyamine-dependent metabolic shielding regulates alternative splicing

Author: Zabala-Letona, Amaia, Pujana-Vaquerizo, Mikel, Martinez-Laosa, Belen, Ponce-Rodriguez, Maria, Garcia-Longarte, Saioa, Mendizabal, Isabel, Gimeno, Ana, Rogalska, Malgorzata, Tan, Joycelyn, Cabrera, Diana, van Liempd, Sebastiaan, Ximenez-Embun, Pilar, Espinosa, Sergio, Fagoaga-Eugui, Maider, Peccati, Francesca, Zakrzewski, Maciej, Astobiza, Ianire, Arana-Castaares, Mikel, Cherkaoui, Sarah, Sendino, Maria, Martn-Barros, Ins, Ercilla, Amaia, Bozal-Basterra, Laura, Carlevaris, Onintza, Arruabarrena-Aristorena, Amaia, Prez-Andrs, Encarnacin, Santamara-Zamorano, Telmo, Ferrer-Bonsoms, Juan A., Carazo, Fernando, Ciela, Maciej, Lobato, Cesar, Seoane, Joan, Martn-Martn, Natalia, Barrio, Rosa, Sutherland, James D., Aransay, Ana M., Falcn-Prez, Juan Manuel, Martnez-Pastor, Barbara, Rubio, Angel, Blanco, Francisco J., Hogarty, Michael D., Morscher, Raphael J., Berra, Edurne, Serwa, Remigiusz A., Jimnez-Barbero, Jess, Jimnez-Oss, Gonzalo, Efeyan, Alejo, Finley, Lydia, Lizcano, Jose M., Muoz, Javier, Valcarcel, Juan, Carracedo, Arkaitz

Issue&Volume: 2026-01-14

Abstract: Metabolites are central to cellular homeostasis. Although much emphasis has been placed on their relevance to meet energetic and biosynthetic demands, metabolic intermediates also function as signalling molecules. Here we show that polyamines, small polycations that are critical to cellular homeostasis1,2,3, regulate the process of alternative pre-mRNA splicing. We find that inhibition of polyamine synthesis increases phosphorylation of spliceosomal proteins, concomitant with perturbation of alternative splicing in cells and tissues. Mechanistically, molecular modelling combined with biochemical assays revealed that polyamines bind to acidic phosphorylatable motifs in splicing factors of the U2 small nuclear ribonucleoprotein SF3 subcomplex, thus preventing the action of upstream kinases. We refer to this molecular process by which polyamines regulate protein phosphorylation as metabolic shielding.

DOI: 10.1038/s41586-025-09965-1

Source: https://www.nature.com/articles/s41586-025-09965-1