Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.
State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, China.
Nat Cell Biol. 2020 Apr;22(4):453-464. doi: 10.1038/s41556-020-0485-0. Epub 2020 Mar 23.
TAZ promotes growth, development and tumorigenesis by regulating the expression of target genes. However, the manner in which TAZ orchestrates the transcriptional responses is poorly defined. Here we demonstrate that TAZ forms nuclear condensates through liquid-liquid phase separation to compartmentalize its DNA-binding cofactor TEAD4, coactivators BRD4 and MED1, and the transcription elongation factor CDK9 for transcription. TAZ forms phase-separated droplets in vitro and liquid-like nuclear condensates in vivo, and this ability is negatively regulated by Hippo signalling through LATS-mediated phosphorylation and is mediated by the coiled-coil (CC) domain. Deletion of the TAZ CC domain or substitution with the YAP CC domain prevents the phase separation of TAZ and its ability to induce the expression of TAZ-specific target genes. Thus, we identify a mechanism of transcriptional activation by TAZ and demonstrate that pathway-specific transcription factors also engage the phase-separation mechanism for efficient and specific transcriptional activation.
TAZ 通过调节靶基因的表达来促进生长、发育和肿瘤发生。然而,TAZ 协调转录反应的方式还不清楚。在这里,我们证明 TAZ 通过液-液相分离形成核凝聚物,将其 DNA 结合辅助因子 TEAD4、共激活因子 BRD4 和 MED1 以及转录延伸因子 CDK9 分隔开来进行转录。TAZ 在体外形成相分离液滴,在体内形成液态核凝聚物,这种能力受到 Hippo 信号通过 LATS 介导的磷酸化的负调控,并且由卷曲螺旋(CC)结构域介导。TAZ 的 CC 结构域缺失或用 YAP 的 CC 结构域取代,会阻止 TAZ 的相分离及其诱导 TAZ 特异性靶基因表达的能力。因此,我们确定了 TAZ 转录激活的一种机制,并证明了通路特异性转录因子也采用相分离机制进行高效和特异性的转录激活。
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