William Dion, Yuren Tao, Maci Chambers, Shanshan Zhao, Riley K Arbuckle, Michelle Sun, Syeda Kubra, Yuhang Nie, Megan Ye, Mads B Larsen, Daniel Camarco, Eleanor Ickes, Claire DuPont, Haokun Wang, Bingjie Wang, Silvia Liu, Shaohua Pi, Bill B Chen, Yuanyuan Chen, Xu Chen, Bokai Zhu
Current treatments targeting individual protein quality control have limited efficacy in alleviating proteinopathies, highlighting the prerequisite for a common upstream druggable target capable of global proteostasis modulation. Building on our prior research establishing nuclear speckles as pivotal organelles responsible for global proteostasis transcriptional control, we aim to alleviate proteinopathies through nuclear speckle rejuvenation. We identified pyrvinium pamoate as a small-molecule nuclear speckle rejuvenator that enhances protein quality control while suppressing YAP1 signaling via decreasing the surface tension of nuclear speckle condensates through interaction with the intrinsically disordered region of nuclear speckle scaffold protein SON...
April 21, 2024: bioRxiv