A chaperone-like function of FUS ensures TAZ condensate dynamics and transcriptional activation
A chaperone-like function of FUS ensures TAZ condensate dynamics and transcriptional activation
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DOI：
10.1038/s41556-023-01309-3
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发表时间：
2024-01
影响因子：
21.3
通讯作者：
Yangqing Shao;Xin Shu;Yi Lu;Wenxuan Zhu;Ran Li;Huanyi Fu;Chengyu Li;Wei Sun;Zhuo Li;Yitong Zhang;Xiaolei Cao;Xifu Ye;Emmanuel Ajiboye;Bin Zhao;Long Zhang;Haifan Wu;Xinhua Feng;Bing Yang;Huasong Lu
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文献类型：
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作者：
Yangqing Shao;Xin Shu;Yi Lu;Wenxuan Zhu;Ran Li;Huanyi Fu;Chengyu Li;Wei Sun;Zhuo Li;Yitong Zhang;Xiaolei Cao;Xifu Ye;Emmanuel Ajiboye;Bin Zhao;Long Zhang;Haifan Wu;Xinhua Feng;Bing Yang;Huasong Lu
河马途径在器官发育、组织动态平衡和肿瘤生长中起着重要作用。它的下游效应子TAZ是一个转录共激活因子，通过形成生物分子缩合物来促进靶基因的表达。然而，调节TAZ凝聚物的生物物理性质以实现河马信号的机制还不是很清楚。在这里，使用化学交联和无偏倚的蛋白质组学方法，我们表明FUS与TAZ缩合物结合，并发挥伴侣般的作用，以保持其适当的流动性和强大的转录活性。从机制上讲，FUS的低复杂性序列结构域以磷酸化调控的方式靶向TAZ的卷曲结构域，这确保了TAZ凝聚物的流动性和动态性。在缺乏FUS的细胞中，TAZ与固定化的TAZ缩合成凝胶状或固体状集合体，导致靶基因表达减少，抑制了促肿瘤活性。因此，我们的发现确定了FUS在河马调控中的伴侣样功能，并证明了适当的转录缩合物的生物物理性质对于基因激活是必不可少的。
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.