Polyamine-dependent metabolic shielding regulates alternative splicing
Amaia Zabala‐Letona, Mikel Pujana-Vaquerizo, Belen Martinez-Laosa, María Ponce-Rodriguez, Saioa Garcia‐Longarte, Isabel Mendizabal, Ana Gimeno, Malgorzata Ewa Rogalska, Joycelyn Tan, Diana Cabrera, Sebastiaan van Liempd, Pilar Ximénez‐Embún, Sergio Espinosa, Maider Fagoaga-Eugui, Francesca Peccati, Maciej Zakrzewski, Ianire Astobiza, Mikel Arana-Castañares, Sarah Cherkaoui, Maria Sendino, Inés Martín-Barros, Amaia Ercilla, Laura Bozal-Basterra, Onintza Carlevaris, Amaia Arruabarrena-Aristorena, Encarnación Pérez-Andrés, Telmo Santamaría-Zamorano, Juan A. Ferrer-Bonsoms, Fernando D. Carazo, Maciej Cieśla, César Lobato, Joan Seoane, Natalia Martin-Martin, Rosa María Palma Barrio, James D. Sutherland, Ana M. Aransay, Juan Manuel Falcón-Pérez, Bárbara Martínez-Pastor, Angel Rubio, Francisco J. Blanco, Michael D. Hogarty, Raphael J. Morscher, Edurne Berra, Remigiusz A. Serwa, Jesús Jiménez-Barbero, Gonzalo Jiménez-Osés, Alejo Efeyan, Lydia W.S. Finley, José M. Lizcano, Javier Muñoz, Juan Valcárcel, Arkaitz Carracedo
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 homeostasis1–3, 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. Polyamines prevent the action of kinases on acidic phosphorylatable motifs in spliceosomal proteins, thus providing a mechanism for metabolite-mediated regulation of alternative splicing in cells.