iProXProteomicsLingqiang ZhangHomo Sapienshttp://www.iprox.org/page/project.html?id=IPX0006338000zhanglq@nic.bmi.ac.cnState Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center of Protein Sciences (Beijing), Beijing Institute of Lifeomics; Beijing, 100850, China.iProXProtein ubiquitination plays a critical role in protein quality control in response to cellular stress. The excessive accumulation of ubiquitinated conjugates can be detrimental to cells and is recognized as a hallmark of multiple neurodegenerative diseases. However, an in-depth understanding of how the excessive ubiquitin chains are removed to maintain ubiquitin homeostasis post stress remains largely unclear. Here we found that caspase-2 (CASP2) accumulates in a ubiquitin and proteasome-positive biomolecular condensate, which we named ubstressome, following stress and functions as a deubiquitinase to remove overloaded ubiquitin chains on proteins prone to misfolding. Mechanistically, CASP2 binds to the poly-ubiquitinated conjugates through its allosteric ubiquitin-interacting motif-like region and decreases overloaded ubiquitin chains in a protease-dependent manner to promote substrate degradation. CASP2 deficiency in mice results in excessive accumulation of poly-ubiquitinated TAR DNA-binding protein 43, leading to motor defects. Our findings uncover a stress-evoked deubiquitinating activity of CASP2 in the maintenance of cellular ubiquitin homeostasis, which differs from the well-known roles of caspase in apoptosis and inflammation. These data also reveal unrecognized protein quality control functions of condensates in the removal of stress-induced ubiquitin chains.Caspase-2 is a condensate-mediated deubiquitinase in protein quality control.Ge Yingwei Y, Zhou Lijie L, Fu Yesheng Y, He Lijuan L, Chen Yi Y, Li Dingchang D, Xie Yuping Y, Yang Jun J, Wu Haitao H, Dai Hongmiao H, Peng Zhiqiang Z, Zhang Yong Y, Yi Shaoqiong S, Wu Bo B, Zhang Xin X, Zhang Yangjun Y, Ying Wantao W, Cui Chun-Ping CP, Liu Cui Hua CH, Zhang Lingqiang LfalseCaspase-2 is a condensate-mediated deubiquitinase in protein quality controlWhen cells encounter proteome stresses, caspase-2 accumulates in a ubiquitin-rich condensate, which functions as a deubiquitinase to cleave the overloaded ubiquitinated proteins.Wed Sep 06 00:00:00 BST 2023PXD041964960639482354