UBE2N Is Essential for Maintenance of Skin Homeostasis and Suppression of Inflammation

UBE2N, a Lys63 ubiquitin-conjugating enzyme, plays critical roles in embryogenesis and immune system development and function. However, its roles in adult epithelial tissue homeostasis and pathogenesis are unclear. We generated conditional mouse models that deleted Ube2n in skin cells in a temporally and spatially controlled manner. We found that Ube2n knockout in the adult skin keratinocytes induced a range of inflammatory skin defects characteristic of psoriatic and actinic keratosis. These included inflammation, epidermal and dermal thickening, parakeratosis, and increased immune cell infiltration as well as signs of edema and blistering. Single-cell transcriptomic analyses and RT-qPCR showed that Ube2n-knockout keratinocytes expressed elevated myeloid cell chemoattractants such as Cxcl1 and Cxcl2 and decreased the homeostatic T lymphocyte chemoattractant Ccl27a. Consistently, the infiltrating immune cells were predominantly myeloid-derived cells, including neutrophils and M1-like macrophages, which expressed high levels of inflammatory cytokines such as Il1β and Il24. Pharmacological blockade of the IL-1 receptor associated kinases (IRAK1/4) alleviated inflammation, epidermal and dermal thickening, and immune infiltration of the Ube2n-mutant skin. Together, these findings highlight a key role of keratinocyte UBE2N in maintenance of epidermal homeostasis and skin immunity and identify IRAK1/4 as potential therapeutic target for inflammatory skin disorders.