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 <i>Ube2n</i> in skin cells in a temporally and spatially controlled manner. We found that <i>Ube2n-</i>knockout (KO) in the adult skin keratinocytes induced a range of inflammatory skin defects characteristic of psoriatic and actinic keratosis. These included eczematous 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 <i>Ube2n</i> KO keratinocytes expressed elevated myeloid cell chemo-attractants such as <i>Cxcl1</i> and <i>Cxcl2</i> and decreased the homeostatic T lymphocyte chemo-attractant, <i>Ccl27a</i>. Consistently, the infiltrating immune cells of <i>Ube2n</i>-KO skin were predominantly myeloid-derived cells including neutrophils and M1-like macrophages that were highly inflammatory, as indicated by expression of <i>Il1β</i> and <i>Il24.</i> Pharmacological blockade of the IL-1 receptor associated kinases (IRAK1/4) alleviated eczema, epidermal and dermal thickening, and immune infiltration of the <i>Ube2n</i> 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.