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Polyamine-dependent metabolic shielding regulates alternative splicing

ABSTRACT: 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 that are essential for cell biology, regulate the process of alternative pre-mRNA splicing. We find that the inhibition of polyamine synthesis increases the phosphorylation of spliceosomal proteins, concomitant with remarkable perturbation of alternative splicing in cells and tissues. Mechanistically, molecular modeling together 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”.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Maria Sendino

LAB HEAD: Javier Muñoz

PROVIDER: PXD065659 | Pride | 2025-11-11

REPOSITORIES: Pride

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			Action	DRS
	20250121_MS_AZL_ProtTotal_Fr4_01.raw	Raw
	20250121_MS_AZL_ProtTotal_Fr4_02.raw	Raw
	20250121_MS_AZL_ProtTotal_Fr5_01.raw	Raw
	20250121_MS_AZL_ProtTotal_Fr5_02.raw	Raw
	20250122_MS_AZL_ProtTotal_Fr1_01.raw	Raw

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Polyamine-dependent metabolic shielding regulates U2 snRNP SF3 subcomplex phosphorylation and alternative splicing

Project description: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 that are essential for cell biology, regulate the process of alternative splicing. We find that inhibition of polyamine synthesis increases the phosphorylation of proteins belonging to the spliceosome, consistent with a remarkable perturbation of alternative splicing in cells and tissues. Mechanistically, polyamines bind to acidic phosphorylatable motifs in splicing factors of the U2 snRNP SF3 subcomplex, thus preventing the action of kinases. In summary, we report a molecular process through which polyamines regulate protein phosphorylation in a phenomenon that we define as metabolic shielding

2025-11-11 | PXD046107 | Pride

Polyamine-dependent metabolic shielding regulates alternative splicing

Project description: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”.

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