Polyamine-dependent metabolic shielding regulates alternative splicing

• 成果类型: Article
• 署名作者: 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-Castanares, Mikel; Cherkaoui, Sarah; Sendino, Maria; Martin-Barros, Ines; Ercilla, Amaia; Bozal-Basterra, Laura; Carlevaris, Onintza; Arruabarrena-Aristorena, Amaia; Perez-Andres, Encarnacion; Santamaria-Zamorano, Telmo; Ferrer-Bonsoms, Juan A.; Carazo, Fernando; Ciesla, Maciej; Lobato, Cesar; Seoane, Joan; Martin-Martin, Natalia; Barrio, Rosa; Sutherland, James D.; Aransay, Ana M.; Falcon-Perez, Juan Manuel; Martinez-Pastor, Barbara; Rubio, Angel; Blanco, Francisco J.; Hogarty, Michael D.; Morscher, Raphael J.; Berra, Edurne; Serwa, Remigiusz A.; Jimenez-Barbero, Jesus; Jimenez-Oses, Gonzalo; Efeyan, Alejo; Finley, Lydia; Lizcano, Jose M.; Munoz, Javier; Valcarcel, Juan; Carracedo, Arkaitz
• 署名单位: CIC bioGUNE; CIBER - Centro de Investigacion Biomedica en Red; CIBERONC; Basque Foundation for Science; Pompeu Fabra University; Barcelona Institute of Science & Technology; Centre de Regulacio Genomica (CRG); Memorial Sloan Kettering Cancer Center; Centro Nacional de Investigaciones Oncologicas (CNIO); Hospital Universitari Vall d'Hebron; Autonomous University of Barcelona; Hospital Universitari Vall d'Hebron; Autonomous University of Barcelona; Vall d'Hebron Institut de Recerca (VHIR); Vall d'Hebron Institut d'Oncologia (VHIO); International Institute of Molecular Mechanisms & Machines Polish Academy of Sciences; University of Zurich; University Children's Hospital Zurich; University of Zurich; University of Basque Country; University of Navarra; University of Navarra; ICREA; Autonomous University of Barcelona; CIBER - Centro de Investigacion Biomedica en Red; CIBEREHD; Centro Nacional de Investigaciones Oncologicas (CNIO); Prince Felipe Research Center; University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; University of Pennsylvania; Pennsylvania Medicine; Pompeu Fabra University; University of Basque Country
• 刊物名称: NATURE
• ISSN/ISSBN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-025-09965-1
• 发表日期: 2026-03-19
• 关键词: PROTEIN-KINASE CK2; analysis reveals; phosphorylation; pluripotency; translation; expression; mutations; AMD1

摘要

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.