Four-dimensional nuclear speckle phase separation dynamics regulate proteostasis.
Four-dimensional nuclear speckle phase separation dynamics regulate proteostasis.
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四维核斑点相分离动力学调节蛋白质稳态。
DOI：
10.1126/sciadv.abl4150
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发表时间：
2022-01-07
期刊：
影响因子：
13.6
通讯作者：
Zhu B
中科院分区：
文献类型：
--
作者：
Dion W;Ballance H;Lee J;Pan Y;Irfan S;Edwards C;Sun M;Zhang J;Zhang X;Liu S;Zhu B
细胞自主的12小时时钟协调核斑点LLPS与蛋白质稳态控制。相分离和生物节律分别在空间和时间维度上控制生物过程，但四维整合的机制仍然难以捉摸。在这里，我们确定了一个进化上保守的XBP 1 s-SON轴，它建立了细胞自主的哺乳动物12小时超日节律的核斑点液-液相分离（LLPS）动力学，与24小时生物钟和细胞周期分开。在清晨/下午早些时候观察到的核斑点支架蛋白SON的较高表达产生弥散和流体核斑点，主动增加它们与染色质的相互作用，转录放大未折叠的蛋白质反应，并防止蛋白质组应激，而在傍晚/上午晚些时候降低SON水平后观察到相反的情况。在整个小鼠寿命期间进一步观察到相关的Son和蛋白质稳定基因表达动态。我们的结果表明，通过调节蛋白质稳态的时间动态，核斑点LLP可能代表了与蛋白质稳态失调相关的病理学的一个先前未确定的（计时）治疗靶点。
A cell-autonomous 12-hour clock coordinates nuclear speckle LLPS with proteostasis control. 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 Son 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.
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影响因子：
48
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