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TAZ 的相分离将转录机制分隔开,从而促进基因表达。

Phase separation of TAZ compartmentalizes the transcription machinery to promote gene expression.

机构信息

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.

出版信息

Nat Cell Biol. 2020 Apr;22(4):453-464. doi: 10.1038/s41556-020-0485-0. Epub 2020 Mar 23.


DOI:10.1038/s41556-020-0485-0
PMID:32203417
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11044910/
Abstract

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.

摘要

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。

相似文献

[1]
Phase separation of TAZ compartmentalizes the transcription machinery to promote gene expression.

Nat Cell Biol. 2020-3-23

[2]
Regulation of Hippo pathway transcription factor TEAD by p38 MAPK-induced cytoplasmic translocation.

Nat Cell Biol. 2017-7-28

[3]
Hippo signaling effectors YAP and TAZ induce Epstein-Barr Virus (EBV) lytic reactivation through TEADs in epithelial cells.

PLoS Pathog. 2021-8

[4]
A chaperone-like function of FUS ensures TAZ condensate dynamics and transcriptional activation.

Nat Cell Biol. 2024-1

[5]
Heat stress activates YAP/TAZ to induce the heat shock transcriptome.

Nat Cell Biol. 2020-12

[6]
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[7]
Cysteine S-Glutathionylation Promotes Stability and Activation of the Hippo Downstream Effector Transcriptional Co-activator with PDZ-binding Motif (TAZ).

J Biol Chem. 2016-5-27

[8]
Hippo Component TAZ Functions as a Co-repressor and Negatively Regulates ΔNp63 Transcription through TEA Domain (TEAD) Transcription Factor.

J Biol Chem. 2015-7-3

[9]
A YAP/TAZ-induced feedback mechanism regulates Hippo pathway homeostasis.

Genes Dev. 2015-6-15

[10]
HERC3 promotes YAP/TAZ stability and tumorigenesis independently of its ubiquitin ligase activity.

EMBO J. 2023-2-15

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[2]
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[3]
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Mol Cancer. 2025-8-23

[4]
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Oncogene. 2025-8-19

[5]
Hippo signaling regulates the nuclear behavior and DNA binding times of YAP and TEAD to control transcription.

Sci Adv. 2025-7-25

[6]
Phase separation of a PKA type I regulatory subunit regulates β-cell function through cAMP compartmentalization.

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[7]
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[8]
Regulation of inflammatory responses by pH-dependent transcriptional condensates.

Cell. 2025-7-12

[9]
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Mol Cell. 2025-6-27

[10]
YAP maintains the dynamics of TDP-43 condensates and antagonizes TDP-43 pathological aggregates.

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本文引用的文献

[1]
Phase separation of YAP reorganizes genome topology for long-term YAP target gene expression.

Nat Cell Biol. 2019-12-2

[2]
New insights into YAP/TAZ nucleo-cytoplasmic shuttling: new cancer therapeutic opportunities?

Mol Oncol. 2019-5-17

[3]
Arabidopsis FLL2 promotes liquid-liquid phase separation of polyadenylation complexes.

Nature. 2019-5-1

[4]
Considerations and Challenges in Studying Liquid-Liquid Phase Separation and Biomolecular Condensates.

Cell. 2019-1-24

[5]
Balanced between order and disorder: a new phase in transcription elongation control and beyond.

Transcription. 2019-6

[6]
The Hippo Pathway Regulates Caveolae Expression and Mediates Flow Response via Caveolae.

Curr Biol. 2018-12-27

[7]
The Hippo Pathway: Biology and Pathophysiology.

Annu Rev Biochem. 2019-12-19

[8]
Transcription Factors Activate Genes through the Phase-Separation Capacity of Their Activation Domains.

Cell. 2018-11-15

[9]
Transcriptional addiction in cancer cells is mediated by YAP/TAZ through BRD4.

Nat Med. 2018-9-17

[10]
The Hippo pathway effector TAZ induces TEAD-dependent liver inflammation and tumors.

Sci Signal. 2018-9-11

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