Ufl1, the only identified E3 ligase in the UFMylation system, is crucial for this ubiquitin-like post-translational modification. UFMylation, involving enzymes like UBA5 (E1-like), UFC1 (E2-like), and Ufl1, regulates various biological processes, including hormone signaling, endocrine regulation, and maintaining cell homeostasis under different cellular stresses such as ER stress, genotoxic stress, and oncogenic stress [2].

In T cells, conditional knockout (cKO) of Ufl1 enhances anti-tumor immunity. Ufl1 promotes PD-1 UFMylation, which antagonizes PD-1 ubiquitination and degradation. Ablation of Ufl1 in T cells reduces PD-1 UFMylation, destabilizes PD-1, and enhances CD8+ T-cell activation, leading to better response to anti-CTLA-4 immunotherapy [1]. In BRCA1/2-deficient cells, Ufl1 localizes to stalled forks upon replication stress, catalyzes PTIP UFMylation, leading to MRE11-mediated replication fork degradation. Loss of Ufl1 confers resistance to PARP inhibitors [3]. In nephron tubules, Ufl1 knockout causes kidney atrophy and interstitial fibrosis due to activation of unfolded protein response and cell apoptosis [5]. In skin, Ufl1 deficiency leads to epidermal thickening, pigmentation, and shortened lifespan by up-regulating Endothelin-1 [4].

In summary, Ufl1 plays diverse and essential roles in multiple biological processes. Gene knockout models, especially KO/CKO mouse models, have been instrumental in revealing its functions in cancer, kidney function, skin pigmentation, and responses to cellular stress, offering potential therapeutic targets for related diseases.