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

Nat Cell Biol. 2024 Nov;26(11):1943-1957. doi: 10.1038/s41556-024-01522-8.

Yingwei Ge ^# ¹, Lijie Zhou ^# ¹ ², Yesheng Fu ^# ¹, Lijuan He ¹, Yi Chen ¹ ³, Dingchang Li ⁴, Yuping Xie ¹, Jun Yang ⁵ ⁶, Haitao Wu ⁵ ⁶, Hongmiao Dai ¹, Zhiqiang Peng ¹ ², Yong Zhang ¹ ² ⁷, Shaoqiong Yi ¹, Bo Wu ¹, Xin Zhang ¹, Yangjun Zhang ¹, Wantao Ying ¹, Chun-Ping Cui ¹, Cui Hua Liu ⁸ ⁹, Lingqiang Zhang ¹⁰

Affiliations

1 State Key Laboratory of Medical Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China.
2 School of Medicine, Tsinghua University, Beijing, China.
3 Department of Pathophysiology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China.
4 Department of General Surgery, The First Medical Centre, Chinese PLA General Hospital, Beijing, China.
5 Department of Neurobiology, Beijing Institute of Basic Medical Sciences, Beijing, China.
6 Chinese Institute for Brain Research, Beijing, China.
7 CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
8 CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China. liucuihua@im.ac.cn.
9 Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China. liucuihua@im.ac.cn.
10 State Key Laboratory of Medical Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China. zhanglq@nic.bmi.ac.cn.
# Contributed equally.

PMID: 39482354 DOI: 10.1038/s41556-024-01522-8

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.

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