Zhu Tianxin, Li Huan, Mao Siwei, Zhu Ying, Cao Hengyi, Zhang Qi, Zhen Ni, Zhang Hanxiao, Tian Yawen, Guo Yan, Sun Tianyue, Li Lingyu, Lu Jiajun, He Hao, Xie Lijuan, Mi Ting, Chen Qi, Zhao Zheng, Jiang Hewei, Lu Wenchao, Yin Baobing, Zhu Jidong, Pan Qiuhui, Xie Jingjing, Zhu Guangya
Lingang Laboratory, Shanghai 200031, China; Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201203, China.
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.
Mol Cell. 2025 Sep 18;85(18):3425-3442.e10. doi: 10.1016/j.molcel.2025.08.014. Epub 2025 Sep 5.
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.
