Proteasome Dysfunction in Basal Keratinocytes Drives Epidermal Disruption and Dermal Inflammation.

Epidermal keratinocyte differentiation and cell death are tightly regulated to maintain skin homeostasis, and their disruption leads to severe skin disorders. Proteasome dysfunction has been implicated in proteasome-associated autoinflammatory syndromes, which are characterized by dermal inflammation, as well as in keratosis linearis with ichthyosis congenita and sclerosing keratoderma syndrome caused by mutations in proteasome maturation protein. However, skin manifestations in proteasome-related disorders have been attributed to distinct cellular origins, rendering it unclear whether keratinocyte-intrinsic proteasome dysfunction is a common driver of both epidermal pathology and dermal inflammation. Here, it is demonstrated that keratinocyte-specific deletion of the standard proteasome subunit β5 results in neonatal lethality associated with complete loss of the epidermis. Inducible deletion of β5 in basal keratinocytes led to impaired epidermal differentiation, reduced proliferation, and apoptosis, accompanied by accumulation of ubiquitinated proteins without evidence of endoplasmic reticulum stress. Notably, proteasome dysfunction induced epidermal hyperplasia with spongiosis, followed by epidermolysis. Although this genetic alteration was restricted to keratinocytes, pronounced infiltration of neutrophils and macrophages was observed in the dermis, together with elevated expression of inflammatory mediators. These findings demonstrate that proteasome dysfunction in basal keratinocytes disrupts epidermal integrity and triggers secondary dermal inflammation, providing insight into the skin pathology associated with proteasome-related disorders.