TOR signaling regulates liquid phase separation of the SMN complex governing snRNP biogenesis.
TOR signaling regulates liquid phase separation of the SMN complex governing snRNP biogenesis.
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DOI：
10.1016/j.celrep.2021.109277
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发表时间：
2021-06
期刊：
影响因子：
8.8
通讯作者：
Maximilian Schilling;A. Prusty;B. Boysen;Felix S. Oppermann;Yannick Riedel;Alma Husedzinovic;H. Rasouli;A. König;Pradhipa Ramanathan;Jürgen Reymann;H. Erfle;H. Daub;U. Fischer;O. Gruss
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文献类型：
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作者：
Maximilian Schilling;A. Prusty;B. Boysen;Felix S. Oppermann;Yannick Riedel;Alma Husedzinovic;H. Rasouli;A. König;Pradhipa Ramanathan;Jürgen Reymann;H. Erfle;H. Daub;U. Fischer;O. Gruss
SMN复合物在促进前mRNA加工UsnRNP的组装中的活性与核Cajal体中复合物的缩合相关。虽然其活性的机制细节已被阐明，但缩合的分子基础仍不清楚。高SMN复合物磷酸化表明广泛的调节。在这里，我们报告了基于siRNA的系统筛选SMN在Cajal小体中凝聚能力的调节剂，并将mTOR和核糖体蛋白S6激酶β-1鉴定为关键调节剂。蛋白质组学分析揭示了SMN复合物亚基中TOR依赖的磷酸化。使用稳定表达或光遗传学控制的磷酸突变体，我们证明，丝氨酸49和63磷酸化的人SMN控制的能力，复杂的凝聚在卡哈尔机构通过液-液相分离。我们的研究结果将SMN复合物凝聚和UsnRNP生物发生与细胞能量水平联系起来，并建议调节TOR信号传导作为治疗SMN相关神经肌肉疾病脊髓性肌萎缩症的合理概念。
The activity of the SMN complex in promoting the assembly of pre-mRNA processing UsnRNPs correlates with condensation of the complex in nuclear Cajal bodies. While mechanistic details of its activity have been elucidated, the molecular basis for condensation remains unclear. High SMN complex phosphorylation suggests extensive regulation. Here, we report on systematic siRNA-based screening for modulators of the capacity of SMN to condense in Cajal bodies and identify mTOR and ribosomal protein S6 kinase β-1 as key regulators. Proteomic analysis reveals TOR-dependent phosphorylations in SMN complex subunits. Using stably expressed or optogenetically controlled phospho mutants, we demonstrate that serine 49 and 63 phosphorylation of human SMN controls the capacity of the complex to condense in Cajal bodies via liquid-liquid phase separation. Our findings link SMN complex condensation and UsnRNP biogenesis to cellular energy levels and suggest modulation of TOR signaling as a rational concept for therapy of the SMN-linked neuromuscular disorder spinal muscular atrophy.