Rapid depletion and super-resolution microscopy reveal dual roles of SRSF5 in coordinating nuclear speckle–paraspeckle crosstalk during cellular stress

Nuclear speckles (NS) and paraspeckles (PS) are adjacent yet distinct nuclear condensates that undergo stress-induced reorganization. Here, we identify a dual role for the splicing factor SRSF5 in coordinating the crosstalk between both condensates. Super-resolution imaging shows that SRSF5, while enriched in NS, also overlaps with the shell of a subset of PS. SRSF5 binds purine-rich sequences at the 5' end of NEAT1_2 promoting its alignment to PS shells and the formation of large PS cluster during stress. We propose that SRSF5 binding occurs transiently during PS maturation and must later be removed from NEAT1_2 by nuclear helicases. Inhibition of this remodeling by rocaglamide A, which locks helicases onto purine-rich RNA leads to the aberrant fusion of PS and NS, which can be partially rescued by acute SRSF5 depletion. Surprisingly, while short-term SRSF5 loss impairs PS formation, prolonged depletion activates a feedback loop involving intron retention and premature polyadenylation of TARDBP, reduction of TDP-43 levels and NEAT1_2 isoform switching, ultimately restoring PS clusters. Our findings reveal that SRSF5 serves both architectural and regulatory roles in PS biogenesis and that helicase-mediated remodeling is essential to maintain PS identity and function under stress. These insights uncover fundamental principles of nuclear body dynamics.

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Publication Details

Journal
Nucleic Acids Research
Published
2025-07-19
DOI
https://doi.org/10.1093/nar/gkaf713
Citations
3
Primary Topic
RNA Research and Splicing
Type
article
Field-Weighted Citation Impact
2.42

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article

Rapid depletion and super-resolution microscopy reveal dual roles of SRSF5 in coordinating nuclear speckle–paraspeckle crosstalk during cellular stress

María Clara Hernández Cañás, David Staněk, Helder Y Nagasse, Ewelina Żebrowska et al.
3 citations
Nucleic Acids Research
RNA Research and Splicing
2.42
article

Rapid depletion and super-resolution microscopy reveal dual roles of SRSF5 in coordinating nuclear speckle–paraspeckle crosstalk during cellular stress

María Clara Hernández Cañás, David Staněk, Helder Y Nagasse, Ewelina Żebrowska, Benjamin Arnold, Jan Keiten‐Schmitz, Ricarda J. Riegger, Mike Heilemann, Kathi Zarnack, Michaela Müller-McNicoll, Ellen Kazumi Okuda, Stefan Müller, Dorothee Dormann, Cem Bakisoglu, Laurell F. Kessler, Mara Rudigier, Christine Krost
article en
3 citations

Abstract

Nuclear speckles (NS) and paraspeckles (PS) are adjacent yet distinct nuclear condensates that undergo stress-induced reorganization. Here, we identify a dual role for the splicing factor SRSF5 in coordinating the crosstalk between both condensates. Super-resolution imaging shows that SRSF5, while enriched in NS, also overlaps with the shell of a subset of PS. SRSF5 binds purine-rich sequences at the 5' end of NEAT1_2 promoting its alignment to PS shells and the formation of large PS cluster during stress. We propose that SRSF5 binding occurs transiently during PS maturation and must later be removed from NEAT1_2 by nuclear helicases. Inhibition of this remodeling by rocaglamide A, which locks helicases onto purine-rich RNA leads to the aberrant fusion of PS and NS, which can be partially rescued by acute SRSF5 depletion. Surprisingly, while short-term SRSF5 loss impairs PS formation, prolonged depletion activates a feedback loop involving intron retention and premature polyadenylation of TARDBP, reduction of TDP-43 levels and NEAT1_2 isoform switching, ultimately restoring PS clusters. Our findings reveal that SRSF5 serves both architectural and regulatory roles in PS biogenesis and that helicase-mediated remodeling is essential to maintain PS identity and function under stress. These insights uncover fundamental principles of nuclear body dynamics.

Nucleic Acids ResearchVol. 53(14)
Goethe University Frankfurt (DE), Goethe-Institute United Kingdom (GB), Johannes Gutenberg University Mainz (DE), Frankfurt Institute for Advanced Studies (DE), University Medical Center of the Johannes Gutenberg University Mainz (DE), Max Planck Institute of Biophysics (DE), Institute of Molecular Genetics (RU), Czech Academy of Sciences, Institute of Molecular Genetics (CZ), Institute of Molecular Biology (DE)
California Department of Fish and Game, Deutscher Akademischer Austauschdienst, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
Openalex Percentile: Top 11%
RNA Research and Splicing
2.42
DOIOpen Access PDFOpenAlex
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