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

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