Four-dimensional nuclear speckle phase separation dynamics regulate proteostasis

Phase separation and biorhythms control biological processes in the spatial and temporal dimensions, respectively, but mechanisms of four-dimensional integration remain elusive. Here, we identified an evolutionarily conserved XBP1s-SON axis that establishes a cell-autonomous mammalian 12-hour ultrad...

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Bibliographic Details
Published in:Science advances 2022-01, Vol.8 (1), p.eabl4150-eabl4150
Main Authors: Dion, William, Ballance, Heather, Lee, Jane, Pan, Yinghong, Irfan, Saad, Edwards, Casey, Sun, Michelle, Zhang, Jing, Zhang, Xin, Liu, Silvia, Zhu, Bokai
Format: Article
Language:English
Subjects:
Biomedicine and Life Sciences
Cell Biology
Molecular Biology
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Summary:Phase separation and biorhythms control biological processes in the spatial and temporal dimensions, respectively, but mechanisms of four-dimensional integration remain elusive. Here, we identified an evolutionarily conserved XBP1s-SON axis that establishes a cell-autonomous mammalian 12-hour ultradian rhythm of nuclear speckle liquid-liquid phase separation (LLPS) dynamics, separate from both the 24-hour circadian clock and the cell cycle. Higher expression of nuclear speckle scaffolding protein SON, observed at early morning/early afternoon, generates diffuse and fluid nuclear speckles, increases their interactions with chromatin proactively, transcriptionally amplifies the unfolded protein response, and protects against proteome stress, whereas the opposites are observed following reduced SON level at early evening/late morning. Correlative and proteostasis gene expression dynamics are further observed across the entire mouse life span. Our results suggest that by modulating the temporal dynamics of proteostasis, the nuclear speckle LLPS may represent a previously unidentified (chrono)-therapeutic target for pathologies associated with dysregulated proteostasis.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.abl4150