2. Academic Validation
  3. Endogenous YAP/TAZ partitioning in TEAD condensates orchestrates the Hippo response

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.
Tianxin Zhu 1,  Huan Li 2,  Siwei Mao 3,  Ying Zhu 4,  Hengyi Cao 5,  Qi Zhang 6,  Ni Zhen 6,  Hanxiao Zhang 7,  Yawen Tian 8,  Yan Guo 8,  Tianyue Sun 8,  Lingyu Li 8,  Jiajun Lu 9,  Hao He 9,  Lijuan Xie 8,  Ting Mi 10,  Qi Chen 8,  Zheng Zhao 4,  Hewei Jiang 8,  Wenchao Lu 8,  Baobing Yin 11,  Jidong Zhu 12,  Qiuhui Pan 13,  Jingjing Xie 14,  Guangya Zhu 15
Affiliations

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.

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