Endogenous YAP/TAZ partitioning in TEAD condensates orchestrates the Hippo response

Tianxin Zhu; Huan Li; Siwei Mao; Ying Zhu; Hengyi Cao; Qi Zhang; Ni Zhen; Hanxiao Zhang; Yawen Tian; Yan Guo; Tianyue Sun; Lingyu Li; Jiajun Lu; Hao He; Lijuan Xie; Ting Mi; Qi Chen; Zheng Zhao; Hewei Jiang; Wenchao Lu; Baobing Yin; Jidong Zhu; Qiuhui Pan; Jingjing Xie; Guangya Zhu

doi:10.1016/j.molcel.2025.08.014

Endogenous YAP/TAZ partitioning in TEAD condensates orchestrates the Hippo response

Mol Cell. 2025 Sep 18;85(18):3425-3442.e10. doi: 10.1016/j.molcel.2025.08.014. Epub 2025 Sep 5.

Authors

Tianxin Zhu¹, Huan Li², Siwei Mao³, Ying Zhu⁴, Hengyi Cao⁵, Qi Zhang⁶, Ni Zhen⁶, Hanxiao Zhang⁷, Yawen Tian⁸, Yan Guo⁸, Tianyue Sun⁸, Lingyu Li⁸, Jiajun Lu⁹, Hao He⁹, Lijuan Xie⁸, Ting Mi¹⁰, Qi Chen⁸, Zheng Zhao⁴, Hewei Jiang⁸, Wenchao Lu⁸, Baobing Yin¹¹, Jidong Zhu¹², Qiuhui Pan¹³, Jingjing Xie¹⁴, Guangya Zhu¹⁵

Affiliations

¹ Lingang Laboratory, Shanghai 200031, China; Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201203, China.
² Lingang Laboratory, Shanghai 200031, China; School of Physical Science and Technology, State Key Laboratory of Advanced Medical Materials and Devices, ShanghaiTech University, Shanghai 201210, China; Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201203, China.
³ Lingang Laboratory, Shanghai 200031, China; Department of Laboratory Medicine, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China.
⁴ Department of General Surgery, Hepatobiliary Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China.
⁵ Fujian Key Laboratory of Drug Target Discovery and Structural and Functional Research, School of Pharmacy, Fujian Medical University, Fuzhou 350122, China.
⁶ Department of Laboratory Medicine, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China.
⁷ Lingang Laboratory, Shanghai 200031, China; Department of General Surgery, Jing'an Branch of Huashan Hospital, Fudan University, Jing'an District Centre Hospital of Shanghai, Shanghai 200040, China.
⁸ Lingang Laboratory, Shanghai 200031, China.
⁹ Etern Biopharma, 1505 Zuchongzhi Road, Shanghai 201203, China.
¹⁰ School of Physical Science and Technology, State Key Laboratory of Advanced Medical Materials and Devices, ShanghaiTech University, Shanghai 201210, China.
¹¹ Department of General Surgery, Hepatobiliary Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China; Department of Hepatobiliary Surgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China.
¹² Etern Biopharma, 1505 Zuchongzhi Road, Shanghai 201203, China. Electronic address: zhujidong@eternbio.com.
¹³ Department of Laboratory Medicine, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China; Faculty of Medical Laboratory Science, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China; Shanghai Key Laboratory of Clinical Molecular Diagnostics for Pediatrics, Shanghai 200127, China. Electronic address: panqiuhui@scmc.com.cn.
¹⁴ School of Physical Science and Technology, State Key Laboratory of Advanced Medical Materials and Devices, ShanghaiTech University, Shanghai 201210, China. Electronic address: xiejj@shanghaitech.edu.cn.
¹⁵ Lingang Laboratory, Shanghai 200031, China. Electronic address: zhugy@lglab.ac.cn.

PMID: 40914169
DOI: 10.1016/j.molcel.2025.08.014

Abstract

YAP/TAZ are transcriptional co-activators that pair with transcription factor TEA/ATTS domains (TEADs) for modulating the Hippo pathway. Previous works propose the potential role of YAP/TAZ phase separation for transcriptional activation, yet the biomolecular basis of endogenous YAP/TAZ-TEAD condensates remains unclear. Here, we dissect their endogenous morphology, revealing that YAP/TAZ are client proteins recruited to TEAD condensates in various human cell lines. TEAD proteins have robust intrinsic potential to undergo phase separation, and YAP/TAZ condensates disappear immediately after losing their interaction with TEADs. Moreover, TEAD condensates serve as central organizing hubs to dynamically concentrate active YAP and other markers of transcriptional activation. Based on this, we revisited a series of recently characterized TEAD inhibitors and identified that VGLL4 represents a critical regulator assisting TEAD central pocket inhibitors. Altogether, we demonstrate a fundamental role of TEAD condensates in spatially regulating YAP/TAZ signaling, underscoring their significance in further deciphering TEAD biology and applications in TEAD-targeted therapy.

Keywords: TEAD; VGLL4; YAP/TAZ; biomolecular condensates; inhibitors.

MeSH terms

Adaptor Proteins, Signal Transducing* / genetics
Adaptor Proteins, Signal Transducing* / metabolism
DNA-Binding Proteins* / genetics
DNA-Binding Proteins* / metabolism
HEK293 Cells
Hippo Signaling Pathway
Humans
Phosphoproteins* / genetics
Phosphoproteins* / metabolism
Protein Binding
Protein Serine-Threonine Kinases* / genetics
Protein Serine-Threonine Kinases* / metabolism
Signal Transduction
TEA Domain Transcription Factors
Transcription Factors* / genetics
Transcription Factors* / metabolism
Transcriptional Activation
Transcriptional Coactivator with PDZ-Binding Motif Proteins
YAP-Signaling Proteins

Substances

Transcription Factors
YAP-Signaling Proteins
YAP1 protein, human
Protein Serine-Threonine Kinases
Adaptor Proteins, Signal Transducing
TEA Domain Transcription Factors
DNA-Binding Proteins
VGLL4 protein, human
Transcriptional Coactivator with PDZ-Binding Motif Proteins
Phosphoproteins