Ubiquitin-like proteins NEDD8 and SUMO2 control epithelial homeostasis, regeneration, and inflammation [RNAseq mouse topical NEDD8i]

Stratified epithelial differentiation involves incompletely understood transcriptional and proteomic remodeling. Multi-omic profiling implicated ubiquitin and related networks in differentiation dynamics. Systematic perturbation of ubiquitin-like machinery uncovered opposite functions of NEDD8 and SUMO2. Knockout mice established essential roles for NEDD8 in progenitor maintenance, skin regeneration, and inflammation, whereas SUMO2 was required for differentiation. Beyond ubiquitin-proteasome-concordant changes, NEDD8 directed proteomic regulation correlated with RNA abundance. Integration of IP-MS with genome-wide suppressor screening revealed context-specific NEDDylated dependencies. Among effectors, HNRNPU emerged as a post-transcriptional regulator of epithelial cell state, whose binding repertoire was modulated by NEDDylation, linking NEDD8 induced proteomic remodeling to RNA regulation. Together, these findings define opposite roles for NEDD8 and SUMO2 in orchestrating epithelial homeostasis, regeneration, and inflammation, underscoring how ubiquitin-like networks govern tissue fate.