Abstract
Start codon variants in ubiquitin ligase KLHL24 lead to a gain-of-function mutant KLHL24-ΔN28, which mediates the excessive degradation of keratin 15, desmin, and keratin 14, resulting in alopecia, cardiopathy, and epidermolysis bullosa syndrome. Patients with alopecia, cardiopathy, and epidermolysis bullosa syndrome normally present atrophic scars after wounds heal, which is rare in KRT14-related epidermolysis bullosa. The mechanisms underlying the formation of atrophic scars in epidermolysis bullosa of patients with alopecia, cardiopathy, and epidermolysis bullosa syndrome remain unclear. This study showed that KLHL24-ΔN28 impaired skin wound healing by excessively degrading vimentin. Heterozygous Klhl24c.3G>T knock-in mice displayed delayed wound healing and decreased wound collagen deposition. We identified vimentin as an unreported substrate of KLHL24. KLHL24-ΔN28 mediated the excessive degradation of vimentin, which failed to maintain efficient fibroblast proliferation and activation during wound healing. Furthermore, by mediating vimentin degradation, KLHL24 can hinder myofibroblast activation, which attenuated bleomycin-induced skin fibrosis. These findings showed the function of KLHL24 in regulating tissue remodeling, atrophic scarring, and fibrosis.