Pyoderma gangrenosum caused by the molecular uncoupling of OTULIN catalytic activity and LUBAC binding.

The pathogenic mechanisms underlying pyoderma gangrenosum (PG) remain unclear. Here we report three patients with PG from two unrelated kindreds with homozygous R57C mutation of the linear deubiquitinase OTULIN. The patients have isolated, pediatric-onset, OTULIN-related PG (ORP). In contrast to OTULIN-related autoinflammatory syndrome (ORAS), caused by mutations affecting the catalytic domain, R57C affects the PUB-interacting motif with distinct biochemical, immunological and clinical consequences. OTULIN-R57C is catalytically active but is unable to bind the linear ubiquitin assembly complex (LUBAC). Patient monocytes show heightened expression of IL1B, and OTULIN-R57C fails to suppress inflammasome activity. Patients have elevated levels of TNF, and their dermal fibroblasts show heightened susceptibility to TNF-dependent cell death. Homozygosity for OTULIN-R57C leads to accumulation of linear ubiquitin and LUBAC autoubiquitination in patients' dermal fibroblasts, consistent with pathogenic LUBAC activity. These findings identify a genetic etiology of isolated PG of childhood. We propose a multifactorial mechanism of ORP, including myeloid IL-1β production and TNF-driven death of skin-resident cells, suggesting that blockade of IL-1β or TNF are therapeutic options in PG.