USP21 deubiquitinates DPYSL2 and enhances its centrosomal abundance to promote cilium formation

Ting Song; Peng Zhou; Fengguo Zhang; Chunli Liu; Xueqing Han; Yiyang Yue; Mingzheng Hu; Shaodong Yan; Qingchao Li; Min Liu; Jun Zhou; Huijie Zhao

doi:10.1016/j.jgg.2025.06.006

USP21 deubiquitinates DPYSL2 and enhances its centrosomal abundance to promote cilium formation

doi: 10.1016/j.jgg.2025.06.006

a. Center for Cell Structure and Function, Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Shandong Normal University, Jinan, Shandong 250014, China;
b. Medical Research and Laboratory Diagnostic Center, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250013, China;
c. Department of Genetics and Cell Biology, State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin 300071, China

基金项目:

We thank Heng Guo (Electron Microscopy Core) and Ying Li (Light Microscopy Core) at Shandong Normal University for their assistance in imaging. We thank Chunhong Yang (Shandong Academy of Agricultural Sciences) for instrumental and technical support. This work was supported by the National Natural Science Foundation of China (32300694, 32270807, 32170829, and 31900538), the Shandong Natural Science Foundation (2022HWYQ-075), and the Taishan Scholar Foundation of Shandong Province (tsqn202211109).

详细信息

通讯作者:
Jun Zhou,E-mail:junzhou@sdnu.edu.cn

Huijie Zhao,E-mail:huijiezhao@sdnu.edu.cn

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出版历程
- 收稿日期: 2025-03-24
- 录用日期: 2025-06-28
- 修回日期: 2025-06-27
- 刊出日期: 2026-02-10

USP21 deubiquitinates DPYSL2 and enhances its centrosomal abundance to promote cilium formation

a. Center for Cell Structure and Function, Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Shandong Normal University, Jinan, Shandong 250014, China;
b. Medical Research and Laboratory Diagnostic Center, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250013, China;
c. Department of Genetics and Cell Biology, State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin 300071, China

Funds:

摘要

摘要: Cilia are microtubule-based organelles projecting from the cell surface with important sensory and motility functions. Ciliary defects are associated with diverse diseases collectively known as ciliopathies. However, the molecular mechanisms that govern ciliogenesis remain not fully understood. Here, we demonstrate that ubiquitin-specific protease 21 (USP21) is indispensable for cilium formation through its deubiquitinating activity. Usp21 knockout mice exhibit ciliary defects in multiple organs, such as the kidney, liver, and trachea. Our data also reveal a constant localization of USP21 at the centrosome and basal body during ciliogenesis. Mechanistically, USP21 interacts with dihydropyrimidinase-like 2 (DPYSL2) at the centrosome and removes lysine 48-linked ubiquitination from DPYSL2. Loss of USP21 leads to the proteasomal degradation of DPYSL2 and causes a significant reduction in its centrosome abundance, ultimately resulting in ciliary defects. These findings thus identify a critical role for the USP21–DPYSL2 axis in ciliogenesis and have important implications for health and disease.
- Cilia /
- Deubiquitination /
- USP21 /
- DPYSL2 /
- Ciliogenesis
Abstract: Cilia are microtubule-based organelles projecting from the cell surface with important sensory and motility functions. Ciliary defects are associated with diverse diseases collectively known as ciliopathies. However, the molecular mechanisms that govern ciliogenesis remain not fully understood. Here, we demonstrate that ubiquitin-specific protease 21 (USP21) is indispensable for cilium formation through its deubiquitinating activity. Usp21 knockout mice exhibit ciliary defects in multiple organs, such as the kidney, liver, and trachea. Our data also reveal a constant localization of USP21 at the centrosome and basal body during ciliogenesis. Mechanistically, USP21 interacts with dihydropyrimidinase-like 2 (DPYSL2) at the centrosome and removes lysine 48-linked ubiquitination from DPYSL2. Loss of USP21 leads to the proteasomal degradation of DPYSL2 and causes a significant reduction in its centrosome abundance, ultimately resulting in ciliary defects. These findings thus identify a critical role for the USP21–DPYSL2 axis in ciliogenesis and have important implications for health and disease.
- Cilia /
- Deubiquitination /
- USP21 /
- DPYSL2 /
- Ciliogenesis

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参考文献(68)

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USP21 deubiquitinates DPYSL2 and enhances its centrosomal abundance to promote cilium formation

doi: 10.1016/j.jgg.2025.06.006

通讯作者:
Jun Zhou,E-mail:junzhou@sdnu.edu.cn

Huijie Zhao,E-mail:huijiezhao@sdnu.edu.cn

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USP21 deubiquitinates DPYSL2 and enhances its centrosomal abundance to promote cilium formation

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目录

留言板

USP21 deubiquitinates DPYSL2 and enhances its centrosomal abundance to promote cilium formation

doi: 10.1016/j.jgg.2025.06.006

通讯作者: Jun Zhou,E-mail:junzhou@sdnu.edu.cn Huijie Zhao,E-mail:huijiezhao@sdnu.edu.cn

计量

出版历程

USP21 deubiquitinates DPYSL2 and enhances its centrosomal abundance to promote cilium formation

计量

出版历程

目录

通讯作者:
Jun Zhou,E-mail:junzhou@sdnu.edu.cn

Huijie Zhao,E-mail:huijiezhao@sdnu.edu.cn