Canonical Wnt induction by OTULIN prevents keratinocyte death and skin inflammation

Loss-of-function mutations in the human OTULIN gene, encoding a deubiquitinase with exclusive specificity for linear ubiquitin chains, cause a severe multi-organ autoinflammatory condition involving the skin1,2. Mice lacking OTULIN selectively in keratinocytes develop inflamed skin lesions that progress into squamous tumours, a phenotype driven by excessive TNF-induced cell death3,4. Previous studies suggested a role for OTULIN in mediating Wnt signalling during development5, but the physiological relevance of this association is unknown. Here, we show that OTULIN promotes Wnt signalling in keratinocytes by regulating the linear ubiquitination status of {beta}-catenin. Stabilisation of {beta}-catenin in OTULIN-deficient keratinocytes prevents progressive skin inflammation in prophylactic and therapeutic settings by blocking keratinocyte death. We demonstrate that linearly ubiquitinated {beta}-catenin accumulates in OTULIN-deficient keratinocytes, promoting its ubiquitination with K48 chains and subsequent proteasomal degradation. Reduced Wnt signalling in OTULIN-deficient keratinocytes leads to degradation of TCF3, an essential survival factor for keratinocytes6. Collectively, our data identify OTULINs linear deubiquitination activity as a key regulator of epithelial cell viability, not only by preventing cell death downstream of TNF, but also by promoting canonical Wnt signalling.