A tale of two tags: UFMylation counters ubiquitination for ciliary homeostasis

Posttranslational modification of proteins by ubiquitin and ubiquitin-like modifiers (UBLs) governs virtually all aspects of cell signalling and physiology, from proteostasis and cell-cycle control to responses to stress and infection [ 1 ]. While the molecular functions of ubiquitination are relatively well characterised, the roles of most UBL modifications remain elusive. In this issue of Cell Death & Differentiation, Wang et al. [ 2 ] uncover a striking example of crosstalk between these two systems. They show that ubiquitin fold modifier 1 (UFM1) [ 3 ] is conjugated to IFT88, a core component of the intraflagellar transport machinery required for cilia assembly, thereby shielding it from ubiquitination-dependent degradation (Fig. 1 ). This UFM1-mediated protection of IFT88 ensures ciliary integrity and tissue homeostasis. Fig. 1: UFL1 is required for ciliary homeostasis. UFM1-specific ligase (UFL1) UFMylates IFT88 on K572. This UFMylation ensures ciliary integrity and function by preventing PJA2-mediated ubiquitination of the same residue and subsequent proteasomal degradation of IFT88. This mutually exclusive modification of K572 reveals an unexpected antagonism between UFMylation and ubiquitination in the regulation of ciliary homeostasis. Figure created in BioRender. Damgaard, RB. (2025) https://biorender.com/3x7ue19 . Full size image