北京生命组学研究所张令强等共同合作，近期取得重要工作进展。他们研究提出，Caspase-2是蛋白质质量控制中由凝结物介导的去泛素酶。相关研究成果2024年10月31日在线发表于《自然—细胞生物学》杂志上。

据介绍，蛋白质泛素化在细胞应激反应中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，对于如何去除过量泛素链以维持应激后泛素稳态的深入理解在很大程度上仍然不清楚。

研究人员发现，CASP2在压力下积聚在泛素和蛋白酶体阳性的生物分子缩合物中，研究人员将其命名为substressome，并作为去泛素酶发挥作用，以去除易发生错误折叠的蛋白质上超载的泛素链。从机制上讲，CASP2通过其变构泛素相互作用基序样区域与聚泛素化偶联物结合，并以蛋白酶依赖的方式减少超载的泛素链，以促进底物降解。小鼠CASP2缺乏导致泛素化TAR DNA结合蛋白43过度积累，导致运动缺陷。

总之，这一研究揭示了CASP2在维持细胞泛素稳态中的应激诱发去泛素化活性，这与众所周知的胱天蛋白酶在凋亡和炎症中的作用不同。这些数据还揭示了凝聚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。

附：英文原文

Title: Caspase-2 is a condensate-mediated deubiquitinase in protein quality control

Author: Ge, Yingwei, Zhou, Lijie, Fu, Yesheng, He, Lijuan, Chen, Yi, Li, Dingchang, Xie, Yuping, Yang, Jun, Wu, Haitao, Dai, Hongmiao, Peng, Zhiqiang, Zhang, Yong, Yi, Shaoqiong, Wu, Bo, Zhang, Xin, Zhang, Yangjun, Ying, Wantao, Cui, Chun-Ping, Liu, Cui Hua, Zhang, Lingqiang

Issue&Volume: 2024-10-31

Abstract: 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.

DOI: 10.1038/s41556-024-01522-8

Source: https://www.nature.com/articles/s41556-024-01522-8