UFMylation orchestrates kidney development through YAP stabilization

The ubiquitin-like modifier UFM1 regulates diverse cellular processes through UFMylation. We previously demonstrated that UFMylation ligase UFL1 deficiency induces endoplasmic reticulum stress and culminates in kidney atrophy in adult mice, yet the critical UFMylation substrates and its function in organogenesis remain largely unexplored. Here, we report UFMylation is required for mammalian kidney development through Yes-associated protein (YAP) stabilization. Genetic ablation of Ufl1 in the murine kidney results in severe dysplasia, phenocopying the loss of YAP activity. We identified YAP as a substrate for UFMylation at lysine 76 (K76), which shields YAP from ubiquitin-proteasome degradation, thereby promoting its nuclear accumulation and transcriptional activation. Additionally, we discovered UFSP1, rather than UFSP2, acted as the primary protease for YAP de-UFMylation, whose depletion promoted YAP stabilization and activation. These findings establish UFMylation as a crucial post-translational mechanism licensing YAP-dependent transcription during development, reveal unexpected complexity in the regulation of YAP UFMylation, and imply a previously unrecognized etiological pathway for kidney dysplasia.