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

© 2025 The Authors. Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China. Published by Elsevier Limited and Science Press.