浙江大学陆华松、杨兵研究组合作提出FUS的伴侣样功能确保TAZ凝聚动力学和转录激活。这一研究成果发表在2024年1月3日出版的国际学术期刊《自然—细胞生物学》上。

通过化学交联结合公正的蛋白质组学方法，他们发现FUS与TAZ凝聚物结合，并发挥类似伴侣的作用，以维持其适当的流动性和强大的转录活性。在机制上，FUS的低复杂性序列结构域以磷酸化调控的方式靶向TAZ的盘绕结构域，从而保证了TAZ凝聚物的流动性和动态性。

在缺乏FUS的细胞中，TAZ凝聚物转变为固定化TAZ的凝胶状或固体状组装物，导致靶基因表达减少和促肿瘤活性抑制。因此，他们的研究结果确定了FUS在Hippo调节中的伴侣样功能，并证明转录凝聚物的适当生物物理特性对基因激活至关重要。

据介绍，Hippo通路在器官发育、组织稳态和肿瘤生长中具有重要作用。其下游效应TAZ是一种转录共激活因子，通过形成生物分子凝聚物促进靶基因表达。然而，调节TAZ凝聚物的生物物理特性以使Hippo信号传导的机制尚不清楚。

附：英文原文

Title: A chaperone-like function of FUS ensures TAZ condensate dynamics and transcriptional activation

Author: Shao, Yangqing, Shu, Xin, Lu, Yi, Zhu, Wenxuan, Li, Ran, Fu, Huanyi, Li, Chengyu, Sun, Wei, Li, Zhuo, Zhang, Yitong, Cao, Xiaolei, Ye, Xifu, Ajiboye, Emmanuel, Zhao, Bin, Zhang, Long, Wu, Haifan, Feng, Xin-Hua, Yang, Bing, Lu, Huasong

Issue&Volume: 2024-01-03

Abstract: The Hippo pathway has important roles in organ development, tissue homeostasis and tumour growth. Its downstream effector TAZ is a transcriptional coactivator that promotes target gene expression through the formation of biomolecular condensates. However, the mechanisms that regulate the biophysical properties of TAZ condensates to enable Hippo signalling are not well understood. Here using chemical crosslinking combined with an unbiased proteomics approach, we show that FUS associates with TAZ condensates and exerts a chaperone-like effect to maintain their proper liquidity and robust transcriptional activity. Mechanistically, the low complexity sequence domain of FUS targets the coiled-coil domain of TAZ in a phosphorylation-regulated manner, which ensures the liquidity and dynamicity of TAZ condensates. In cells lacking FUS, TAZ condensates transition into gel-like or solid-like assembles with immobilized TAZ, which leads to reduced expression of target genes and inhibition of pro-tumorigenic activity. Thus, our findings identify a chaperone-like function of FUS in Hippo regulation and demonstrate that appropriate biophysical properties of transcriptional condensates are essential for gene activation.

DOI: 10.1038/s41556-023-01309-3

Source: https://www.nature.com/articles/s41556-023-01309-3