Polyamine-dependent metabolic shielding regulates alternative splicing.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 41535471.
- Also identified by DOI 10.1038/s41586-025-09965-1 and PMC identifier 12999471.
- Licence recorded as CC BY-NC-ND.
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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 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.
Medical subject headings
- Alternative Splicing
- Phosphorylation
- Polyamines
- Proteins