From Gene to Lesion: Mechanistic Insights into OTULIN R57C-Driven Isolated Pyoderma Gangrenosum of Childhood

Abstract

Pyoderma gangrenosum (PG) is an extremely rare and severe inflammatory skin disorder. For the first time, we define a monogenic etiology for childhood PG resulting from bi-allelic mutations in the human gene OTULIN. We report patients with recurrent PG since childhood, each with a homozygous OTULIN R57C mutation. OTULIN encodes a deubiquitinase that cleaves linear ubiquitin chains added to proteins by the linear ubiquitin chain assembly complex (LUBAC). This balance between removing and adding linear ubiquitin is crucial to regulating immune signaling. Other bi-allelic mutations in OTULIN result in a fatal systemic autoinflammatory disorder called OTULIN-related autoinflammatory syndrome (ORAS), while rare mono-allelic OTULIN mutations leads to defective skin immunity to Staphylococcus aureus infections. All previously reported mutations in OTULIN affect the catalytic domain and compromise deubiquitinase function, leading to hyperactive NF-kB activity. In contrast, the R57C mutation affects a domain responsible for protein-protein interactions. We demonstrate that R57C reduces OTULIN’s ability to bind LUBAC but preserves its deubiquitinase activity. Patients with the R57C OTULIN mutation show gene expression patterns distinct from patients with catalytically dead OTULIN or healthy controls. Further, the patients show dysregulated IL-1B transcription in monocytes and production in whole blood. In the skin, OTULIN-KO human keratinocytes are susceptible to TNF-induced cell death, which we hypothesize is due to dysregulated TNF-dependent signaling rather than availability of cytokine receptors. These discoveries add to the emerging spectrum of inborn errors of immunity caused by defects in linear ubiquitin regulation and suggests a role for OTULIN in maintaining skin immune homeostasis.