Protein 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.

蛋白质泛素化在响应细胞应激的蛋白质质量控制中起着关键作用。泛素化偶联物的过度积累可能对细胞有害，被认为是多种神经退行性疾病的标志。然而，对如何去除过多的泛素链以维持应激后泛素稳态的深入了解在很大程度上仍不清楚。在这里，我们发现 caspase-2 （CASP2） 在胁迫后积累在泛素和蛋白酶体阳性生物分子缩合物中，我们将其命名为 ubstressome，并作为去泛素酶发挥作用，以去除容易错误折叠的蛋白质上过载的泛素链。从机制上讲，CASP2 通过其变构泛素相互作用基序样区域与多泛素偶联物结合，并以蛋白酶依赖性方式减少过载的泛素链，以促进底物降解。小鼠的 CASP2 缺陷导致多泛素化的 TAR DNA 结合蛋白 43 的过度积累，从而导致运动缺陷。我们的研究结果揭示了 CASP2 在维持细胞泛素稳态中的应激诱发去泛素化活性，这与众所周知的 caspase 在细胞凋亡和炎症中的作用不同。这些数据还揭示了缩合物在去除应激诱导的泛素链方面未被认识的蛋白质质量控制功能。