2. Academic Validation
  3. Pyoderma gangrenosum caused by the molecular uncoupling of OTULIN catalytic activity and LUBAC binding

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

  • Nat Immunol. 2026 Jun 15. doi: 10.1038/s41590-026-02568-6.
Barathram Swaminathan # 1,  Hwi M Gil # 2,  Sagar Bhattad # 3 4,  Jyothi Janardhanan 3,  Gerardo Mejía Baltodano 5,  Christine Mariskanish 2 6,  Shamel Basaria 2,  Joseph M Choi 2,  Qi Liu 2,  Lisette M Scheepmaker 1,  Mohamud Mohamed 2,  Bertrand Boisson 7 8 9,  Jean-Laurent Casanova 7 8 9 10 11,  Ivona Aksentijevich 12,  András N Spaan 13,  Janet G Markle 14 15
Affiliations

Affiliations

  • 1 Department of Medical Microbiology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
  • 2 Division of Molecular Pathogenesis, Department of Pathology, Microbiology & Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 3 Division of Pediatric Immunology and Rheumatology, Department of Pediatrics, Aster CMI Hospital, Bengaluru, India.
  • 4 Pediatric Immunology, Rheumatology and BMT, Manipal Hospital - Yelahanka, Bengaluru, India.
  • 5 National Head of Genetics Specialty, Ministerio de Salud, Managua, Nicaragua.
  • 6 Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 7 St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, NY, USA.
  • 8 Laboratory of Human Genetics of Infectious Diseases, INSERM UMR1163, Paris, France.
  • 9 Imagine Institute, University of Paris Cité, Paris, France.
  • 10 Department of Pediatrics, Necker Hospital for Sick Children, Paris, France.
  • 11 Howard Hughes Medical Institute, New York, NY, USA.
  • 12 Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
  • 13 Department of Medical Microbiology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands. [email protected].
  • 14 Division of Molecular Pathogenesis, Department of Pathology, Microbiology & Immunology, Vanderbilt University Medical Center, Nashville, TN, USA. [email protected].
  • 15 Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. [email protected].
  • # Contributed equally.
PMID: 42297973 DOI: 10.1038/s41590-026-02568-6
Abstract

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.

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