OTULIN is a deubiquitinase that specifically cleaves linear ubiquitin chains. We demonstrate that ablation of OTULIN selectively in keratinocytes, results in the appearance of inflammatory skin lesions that develop into verrucous carcinomas. Genetic ablation of TNFR1, knockin expression of kinase-inactive RIPK1 or keratinocyte-specific deletion of FADD and MLKL completely rescues mice with OTULIN deficiency from dermatitis and tumorigenesis, identifying keratinocyte cell death as the driving force for inflammation. Single-cell RNA-sequencing of non-lesional and lesional skin reveals changes in epidermal stem cell identity in OTULIN-deficient keratinocytes prior to substantial immune cell infiltration. Keratinocytes lacking OTULIN display a type-1 interferon and IL-1b response signature, and genetic or pharmacologic inhibition of these cytokines partially inhibits skin inflammation. Finally, expression of a hypomorphic mutant OTULIN allele, previously shown to cause OTULIN-related autoinflammatory syndrome in humans, induces a similar inflammatory phenotype, confirming the paramount importance of OTULIN for restraining skin inflammation and maintaining immune homeostasis.

ESDR206 - OTULIN maintains skin homeostasis by controlling keratinocyte death and stem cell identity

50th Annual Meeting of the European Society for Dermatological Research. VIRTUAL MEETING