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

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.

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Journal
Nature Cell Biology
Published
2024-10-31
DOI
https://doi.org/10.1038/s41556-024-01522-8
Citations
10
Primary Topic
Ubiquitin and proteasome pathways
Type
article
Field-Weighted Citation Impact
2.34
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article

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

Dingchang Li, Zhiqiang Peng, Wantao Ying, Cui Hua Liu et al.
10 citations
Nature Cell Biology
Ubiquitin and proteasome pathways
2.34
article

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

Dingchang Li, Zhiqiang Peng, Wantao Ying, Cui Hua Liu, Lingqiang Zhang, Lijie Zhou, Yingwei Ge, Yong Zhang, Chun‐Ping Cui, Yangjun Zhang, Hongmiao Dai, Yesheng Fu, Yi Chen, Bo Wu, Xintong Zhang, Yuping Xie, Jun Yang, Lijuan He, Haitao Wu, Shaoqiong Yi
article en
10 citations

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.

Nature Cell BiologyVol. 26(11)
Beijing Institute of Education (CN), Anhui Medical University (CN), Chinese Academy of Sciences (CN), Chinese PLA General Hospital (CN), Chinese Institute for Brain Research (CN), Czech Academy of Sciences, Institute of Microbiology (CZ), Institute of Microbiology (CN), Beijing Proteome Research Center (CN), University of Chinese Academy of Sciences (CN), Institute of Basic Medical Sciences of the Chinese Academy of Medical Sciences, Tsinghua University (CN)
Zero hunger
Openalex Percentile: Top 11%
Ubiquitin and proteasome pathways
2.34
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