2. Academic Validation
  3. USP21 deubiquitinates DPYSL2 and enhances its centrosomal abundance to promote cilium formation

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

  • J Genet Genomics. 2025 Jul 5:S1673-8527(25)00193-6. doi: 10.1016/j.jgg.2025.06.006.
Ting Song 1,  Peng Zhou 1,  Fengguo Zhang 2,  Chunli Liu 1,  Xueqing Han 1,  Yiyang Yue 1,  Mingzheng Hu 3,  Shaodong Yan 3,  Qingchao Li 1,  Min Liu 1,  Jun Zhou 4,  Huijie Zhao 5
Affiliations

Affiliations

  • 1 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.
  • 2 Medical Research and Laboratory Diagnostic Center, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250013, China.
  • 3 Department of Genetics and Cell Biology, State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin 300071, China.
  • 4 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; Department of Genetics and Cell Biology, State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin 300071, China. Electronic address: junzhou@sdnu.edu.cn.
  • 5 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. Electronic address: huijiezhao@sdnu.edu.cn.
PMID: 40619097 DOI: 10.1016/j.jgg.2025.06.006
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. Herein, 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.

Keywords

Cilia; Ciliogenesis; DPYSL2; Deubiquitination; USP21.

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