Polyamine-dependent metabolic shielding regulates alternative splicing

Metabolites are central to cellular homeostasis. Whereas much emphasis has been placed on their relevance to meet energetic and biosynthetic demands, metabolic intermediates also function as signaling molecules. Here we show that polyamines, small polycations critical to cellular homeostasis1-3, regulate the process of alternative pre-mRNA splicing. We find that the inhibition of polyamine synthesis increases the phosphorylation of spliceosomal proteins, concomitant with a remarkable perturbation of alternative splicing in cells and tissues. Mechanistically, molecular modeling combined with biochemical assays revealed that polyamines bind to acidic phosphorylatable motifs in splicing factors of the U2 snRNP SF3 subcomplex, thus preventing the action of kinases. The molecular process through which polyamines regulate protein phosphorylation is a phenomenon that we define as “metabolic shielding”.