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<p>UFMylation, a post-translational modification involving the covalent conjugation of ubiquitin-fold modifier 1 (UFM1) to target proteins, has been implicated in a wide spectrum of human diseases. However, the underlying molecular mechanisms are poorly understood. Herein, we demonstrate that UFM1-specific ligase 1 (UFL1), the sole ligase for UFMylation, is indispensable for ciliary homeostasis. Genetic ablation of UFL1 in mice results in severe defects in ciliary structure and function in multiple tissues. Mechanistic investigation reveals that intraflagellar transport 88 (IFT88), a protein essential for ciliary assembly and maintenance, undergoes UFMylation at lysine 572. The UFMylation antagonizes IFT88 ubiquitination by Praja ring finger ubiquitin ligase 2 (PJA2), thereby preventing its proteasomal degradation. The lysine 572-to-arginine mutant of IFT88 exhibits increased stability and efficacy in rescuing ciliary defects induced by UFL1 depletion. Our findings identify a critical role for IFT88 UFMylation in ciliary homeostasis and offer novel insights into human ciliopathies.</p>

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UFL1-mediated UFMylation antagonizes IFT88 ubiquitination and degradation to maintain ciliary homeostasis

  • 期刊论文

  • 发表日期：

    2025年11月21日

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  • Runa Wang,
  • Guizhi Guo,
  • Renshuai Zhang,
  • Lin Li,
  • Yingxin Gong,
  • Long Yin,
  • Shuhua Li,
  • Changfeng Wei,
  • Jun Zhou,
  • Min Liu,
  • Jie Ran

摘要

UFMylation, a post-translational modification involving the covalent conjugation of ubiquitin-fold modifier 1 (UFM1) to target proteins, has been implicated in a wide spectrum of human diseases. However, the underlying molecular mechanisms are poorly understood. Herein, we demonstrate that UFM1-specific ligase 1 (UFL1), the sole ligase for UFMylation, is indispensable for ciliary homeostasis. Genetic ablation of UFL1 in mice results in severe defects in ciliary structure and function in multiple tissues. Mechanistic investigation reveals that intraflagellar transport 88 (IFT88), a protein essential for ciliary assembly and maintenance, undergoes UFMylation at lysine 572. The UFMylation antagonizes IFT88 ubiquitination by Praja ring finger ubiquitin ligase 2 (PJA2), thereby preventing its proteasomal degradation. The lysine 572-to-arginine mutant of IFT88 exhibits increased stability and efficacy in rescuing ciliary defects induced by UFL1 depletion. Our findings identify a critical role for IFT88 UFMylation in ciliary homeostasis and offer novel insights into human ciliopathies.