Material properties of phase-separated TFEB condensates regulate the autophagy-lysosome pathway.
Material properties of phase-separated TFEB condensates regulate the autophagy-lysosome pathway.
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相分离 TFEB 缩合物的材料特性调节自噬-溶酶体途径
DOI：
10.1083/jcb.202112024
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发表时间：
2022-05-02
期刊：
影响因子：
--
通讯作者：
Zhang H
中科院分区：
文献类型：
--
作者：
Wang Z;Chen D;Guan D;Liang X;Xue J;Zhao H;Song G;Lou J;He Y;Zhang H
蛋白质缩合物具有独特的物质特性。Wang等人。结果表明，TFEB缩合物的材料性质决定了它们的大小和转录活性。这些特性可以被操纵来调节TFEB在自噬-溶酶体途径中的活性。通过液-液相分离(LLP)组装的蛋白质凝聚体的材料性质是如何保持并影响生理功能的，人们知之甚少。在这里，我们显示了转录因子TFEB的液体状凝聚物在体外和活细胞中表现出低融合倾向。我们直接测量了液滴之间的引力，并表征了TFEB凝聚物的界面张力、粘度和弹性。TFEB凝析油含有严格的界面，控制着它们的相互作用行为。包括Ro-3306在内的几个小分子改变了TFEB凝析油的材料性质，增加了它们的尺寸和融合倾向。这些化合物以TFEB依赖的方式促进溶酶体的生物发生和功能，而不改变其胞质-核转位。RO-3306促进自噬活性，促进有毒蛋白质聚集体的降解。我们的研究有助于解释蛋白质凝聚体是如何作为物理上独立的实体保持的，并揭示了TFEB凝聚体的材料属性可以被利用来调节TFEB的活性。
Protein condensates possess distinct material properties. Wang et al. show that the material properties of TFEB condensates govern their size and transcriptional activity. These properties can be manipulated to modulate the activity of TFEB in the autophagy-lysosome pathway. Very little is known about how the material properties of protein condensates assembled via liquid–liquid phase separation (LLPS) are maintained and affect physiological functions. Here we show that liquid-like condensates of the transcription factor TFEB exhibit low fusion propensity in vitro and in living cells. We directly measured the attraction force between droplets, and we characterized the interfacial tension, viscosity, and elasticity of TFEB condensates. TFEB condensates contain rigid interfacial boundaries that govern their interaction behaviors. Several small molecules, including Ro-3306, modify the material properties of TFEB condensates, increasing their size and fusion propensity. These compounds promote lysosomal biogenesis and function in a TFEB-dependent manner without changing its cytoplasmic-nuclear translocation. Ro-3306 promotes autophagy activity, facilitating degradation of toxic protein aggregates. Our study helps explain how protein condensates are maintained as physically separate entities and reveals that the material properties of TFEB condensates can be harnessed to modulate TFEB activity.
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