Polyamine-dependent metabolic shielding regulates alternative splicing
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 homeostasis<sup>1-3</sup>, 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.
Authors
- Amaia Arruabarrena-Aristorena (ORCID: https://orcid.org/0000-0002-1636-3944)
- José M. Lizcano (ORCID: https://orcid.org/0000-0002-3154-5383)
- Lydia W.S. Finley (ORCID: https://orcid.org/0000-0003-4023-7574)
- César Lobato
- Bárbara Martínez-Pastor (ORCID: https://orcid.org/0000-0003-0960-1737)
- Amaia Ercilla (ORCID: https://orcid.org/0000-0001-8999-7131)
- Natalia Martin-Martin
- Angel Rubio
- Mikel Pujana-Vaquerizo (ORCID: https://orcid.org/0000-0001-8783-5075)
- Juan Valcárcel (ORCID: https://orcid.org/0000-0001-5398-3571)
- Amaia Zabala‐Letona (ORCID: https://orcid.org/0000-0003-2088-5195)
- Pilar Ximénez‐Embún (ORCID: https://orcid.org/0000-0002-2582-9443)
- Michael D. Hogarty (ORCID: https://orcid.org/0000-0002-9221-4852)
- Onintza Carlevaris (ORCID: https://orcid.org/0000-0002-8616-6233)
- Francesca Peccati (ORCID: https://orcid.org/0000-0002-7813-8216)
- Edurne Berra (ORCID: https://orcid.org/0000-0002-3820-5744)
- Alejo Efeyan (ORCID: https://orcid.org/0000-0002-3806-6799)
- Encarnación Pérez-Andrés (ORCID: https://orcid.org/0000-0003-1459-8966)
- Fernando D. Carazo (ORCID: https://orcid.org/0000-0002-2580-5337)
- Javier Muñoz
- Sarah Cherkaoui (ORCID: https://orcid.org/0000-0002-0636-4177)
- Malgorzata Ewa Rogalska (ORCID: https://orcid.org/0000-0002-6331-9815)
- James D. Sutherland (ORCID: https://orcid.org/0000-0003-3229-793X)
- Ana M. Aransay (ORCID: https://orcid.org/0000-0002-8271-612X)
- Maciej Cieśla (ORCID: https://orcid.org/0000-0002-8460-1991)
- Saioa Garcia‐Longarte (ORCID: https://orcid.org/0000-0001-5412-4234)
- Inés Martín-Barros
- Rosa María Palma Barrio (ORCID: https://orcid.org/0000-0002-7282-993X)
- Maider Fagoaga-Eugui
- Maciej Zakrzewski (ORCID: https://orcid.org/0000-0002-8736-6755)
- Joan Seoane
- María Ponce-Rodriguez
- Telmo Santamaría-Zamorano
- Ana Gimeno
- Laura Bozal-Basterra
- Joycelyn Tan
- Juan A. Ferrer-Bonsoms
- Mikel Arana-Castañares
- Ianire Astobiza
- Gonzalo Jiménez-Osés
- Remigiusz A. Serwa
- Sergio Espinosa
- Raphael J. Morscher
- Francisco J. Blanco
- Sebastiaan van Liempd
- Maria Sendino
- Juan Manuel Falcón-Pérez
- Belen Martinez-Laosa
- Diana Cabrera
- Arkaitz Carracedo
Institutions
- Ikerbasque (ES)
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Universitat Autònoma de Barcelona (ES)
- Memorial Sloan Kettering Cancer Center (US)
- Children's Hospital of Philadelphia (US)
- University of the Basque Country (ES)
- Universitat Pompeu Fabra (ES)
- BioCruces Health research Institute (ES)
- Spanish National Cancer Research Centre (ES)
- Vall d'Hebron Institut de Recerca (ES)
- CIC bioGUNE (ES)
- University Children's Hospital Zurich (CH)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (ES)
- Centre for Genomic Regulation (ES)
- Centro de Investigación del Cáncer (ES)
- Instituto de Biomedicina de Valencia (ES)
- Centro de Investigación Biomédica en Red de Cáncer (ES)
- Centro de Investigacion Principe Felipe (ES)
- University of Pennsylvania (US)
- Universidad de Navarra (ES)
- Polish Academy of Sciences (PL)
Publication Details
- Journal
- Nature
- Published
- 2026-01-14
- DOI
- https://doi.org/10.1038/s41586-025-09965-1
- Citations
- 2
- Primary Topic
- Polyamine Metabolism and Applications
- Type
- article
- Field-Weighted Citation Impact
- 44.47