2. Academic Validation
  3. Phosphorylation of a nuclear condensate regulates cohesion and mRNA retention

Phosphorylation of a nuclear condensate regulates cohesion and mRNA retention

  • Nat Commun. 2025 Jan 4;16(1):390. doi: 10.1038/s41467-024-55469-3.
Alexa B R McIntyre # 1,  Adrian Beat Tschan # 2 3,  Katrina Meyer 2 4,  Severin Walser 2 5,  Arpan Kumar Rai 2,  Keisuke Fujita 2 6,  Lucas Pelkmans 7
Affiliations

Affiliations

  • 1 Department of Molecular Life Sciences, University of Zurich, Zurich, Switzerland. abmcintyre@bwh.harvard.edu.
  • 2 Department of Molecular Life Sciences, University of Zurich, Zurich, Switzerland.
  • 3 Systems Biology PhD program, Life Science Zurich Graduate School, University of Zurich, Zurich, Switzerland.
  • 4 Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin, Germany.
  • 5 Division of Immunology, University Children's Hospital Zurich, Zurich, Switzerland.
  • 6 Premium Research Institute for Human Metaverse Medicine (WPI-PRIMe), Osaka University, Osaka, Japan.
  • 7 Department of Molecular Life Sciences, University of Zurich, Zurich, Switzerland. lucas.pelkmans@mls.uzh.ch.
  • # Contributed equally.
PMID: 39755675 DOI: 10.1038/s41467-024-55469-3
Abstract

Nuclear speckles are membraneless organelles that associate with active transcription sites and participate in post-transcriptional mRNA processing. During the cell cycle, nuclear speckles dissolve following phosphorylation of their protein components. Here, we identify the PP1 family as the phosphatases that counteract kinase-mediated dissolution. PP1 overexpression increases speckle cohesion and leads to retention of mRNA within speckles and the nucleus. Using APEX2 proximity labeling combined with RNA-sequencing, we characterize the recruitment of specific RNAs. We find that many transcripts are preferentially enriched within nuclear speckles compared to the nucleoplasm, particularly chromatin- and nucleus-associated transcripts. While total polyadenylated RNA retention increases with nuclear speckle cohesion, the ratios of most mRNA species to each Other are constant, indicating non-selective retention. We further find that cellular responses to heat shock, oxidative stress, and hypoxia include changes to the phosphorylation and cohesion of nuclear speckles and to mRNA retention. Our results demonstrate that tuning the material properties of nuclear speckles provides a mechanism for the acute control of mRNA localization.

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