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Nuclear Speckle Dynamics are Controlled by Polyphosphate Inhibition of CLK Proteins

ABSTRACT: Nuclear speckles (NS) are membrane-less nuclear organelles that act as critical hubs for pre-mRNA splicing. Defects in splicing are linked to several human diseases, including cancer, Alzheimer's disease, and dystrophies. While CLK kinases regulate the mobilization of splicing factors from NS, the molecular mechanisms underlying NS assembly and dissolution remain unclear. Using an adaptation of the Biotinylation by Antibody Recognition (BAR) technique, we identified polyphosphate (polyP) as a novel and essential regulator of NS dynamics. Polyphosphate, a highly conserved polyanion composed of a chain of phosphate molecules, is involved in several functions in mammalian cells. Here, we show that polyP interacts with the NS core component SRRM2, and its depletion disrupts NS organization releasing splicing factors into the nucleoplasm. RNA-seq analysis reveals that polyP depletion increases exon exclusion, particularly in transcripts with multiple isoforms, highlighting its role in splicing regulation. Mechanistically, we demonstrate that polyP acts as a physiological inhibitor of CLK3 kinase, preventing the phosphorylation of SR proteins and thereby maintaining NS stability. Our findings not only expand our understanding of NS biology but also provide new insights into the polyP involvement in splicing-related diseases.

ORGANISM(S): Homo sapiens

PROVIDER: GSE325650 | GEO | 2026/03/23

REPOSITORIES: GEO

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Project description:Polyphosphate (polyP) is a ubiquitous and abundant compound found in bacteria, fungi, algae, plant, and animals. Among roles of intracellular polyP in bacteria are resistance and survival in the stationary phase of the growth against stress and stringent condition. Therefore, intracellular polyP is considered as a virulence factor of bacteria. In contrast, exogenous polyP has an antimicrobial activity against a variety of microorganisms. To date, much has been numerous studies of antibacterial effect of polyP against gram positive bacteria and fungi while relatively little reports have been published concerning gram negative bacteria. Here we describe bactericidal effect of polyP against gram negative periodontopathic bacterium, Porphyromonas gingivalis, and the transcriptional change by polyP in this bacterium. The bacterial growth was inhibited by polyP (chain length of P3~P75) at concentration of 0.02~0.03%, but not by Pi and PPi at the concentrations. polyP75 was chosen for further experiments, which suppressed the further growth of P. gingivalis as low as 0.03%. polyP75 completely killed the bacterial cells at the concentration of 0.035%. Microarray analysis was employed to identify genes that showed a greater than 1.5-fold difference in the expression by polyP75 at the concentration of 0.03%. It was found that 155 genes were up-regulated and 173 were down-regulated. Down-regulated genes include groups of energy metabolism-related genes, cell envelope-related genes, and genes in relation to biosynthesis of cofactors, prosthetic groups and carriers. Among the down-regulated genes were several involved in DNA replication, cell division protein, and biosynthesis of purines, pyrimidines, nucleosides and nucleotides. In contrast, a large number of ribosomal proteins, transciptional regulators and transposases were up-regulated. Oxidative stress-related genes and iron storage proteins also appeared to be increased in the expression. Real-time PCR confirmed up- and down-regulation of some selected genes. The overall results suggest that polyP has a bactericidal activity against P. gingivalis, interfering with translation, energy metabolism, DNA replication, cell division, and biosynthesis of purines, pyrimidines, nucleoside and nucleotides. polyP may be used as an agent for prevention and treatment of periodontal infections. Polyp-treated vs. untreated intensity ratio data linked below as a supplementary file. Keywords: agent response

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Nuclear Speckle Dynamics are Controlled by Polyphosphate Inhibition of CLK Proteins

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