Balancing the skin: antagonistic ubiquitin-like signaling pathways govern epidermal homeostasis

In a recent study published in Science , Winge et al. identified the ubiquitin-like modifiers NEDD8 and SUMO2 as antagonistic regulators of epidermal homeostasis, revealing an unexpected role for ubiquitin-like signaling in epidermal cell fate and tissue repair (Fig. 1a ). 1 Fig. 1 Full size image Antagonistic NEDD8 and SUMO2 signaling regulates epidermal homeostasis, regeneration, and inflammatory responses. a Balanced ubiquitin-like (UBL) signaling maintains epidermal homeostasis by coordinating the opposing functions of NEDD8 (Neural precursor cell expressed developmentally downregulated protein 8) and SUMO2 (Small ubiquitin-like modifier 2). NEDD8 preserves the progenitor state, supporting proliferation, self-renewal, wound healing, and inflammatory control, whereas SUMO2 promotes terminal keratinocyte differentiation, epidermal barrier formation, and immune tolerance. b Selection of the multiomic and functional approaches used in this study, including quantitative proteomics, di-glycine remnant immunoprecipitation-mass spectrometry (diGly IP-MS), Perturb-seq, spatial transcriptomics, and in vivo genetic models. c Keratinocyte-specific deletion of Nedd8 induces premature differentiation, epidermal hyperplasia, impaired wound healing, persistent inflammation, and neutrophil recruitment, whereas Sumo2 deficiency disrupts epidermal stratification, compromises barrier function, and promotes dermal T-cell infiltration. d Mechanistically, NEDD8 loss activates NRF2-dependent inflammatory signaling, inducing expression of neutrophil-recruiting mediators, including IL36G , IL1RL1 , IL1A , and CXCL1/8 . e Beyond its canonical role in ubiquitin-proteasome signaling, NEDDylation regulates HNRNPU (Heterogeneous nuclear ribonucleoprotein U)-dependent RNA stabilization. Intact NEDDylation promotes stabilization of progenitor-associated transcripts, whereas loss of NEDDylation redirects HNRNPU toward differentiation-associated mRNAs, thereby controlling epithelial cell fate. Figure created with BioRender.com