The Deubiquitinase OTULIN Is an Essential Negative Regulator of Inflammation and Autoimmunity

Rune Busk Damgaard, Jennifer A Walker, Paola Marco-Casanova, Neil V Morgan, Hannah L Titheradge, Paul R Elliott, Duncan McHale, Eamonn R Maher, Andrew N J McKenzie, David Komander

Research output: Contribution to journalArticlepeer-review


Methionine-1 (M1)-linked ubiquitin chains regulate the activity of NF-κB, immune homeostasis, and responses to infection. The importance of negative regulators of M1-linked chains in vivo remains poorly understood. Here, we show that the M1-specific deubiquitinase OTULIN is essential for preventing TNF-associated systemic inflammation in humans and mice. A homozygous hypomorphic mutation in human OTULIN causes a potentially fatal autoinflammatory condition termed OTULIN-related autoinflammatory syndrome (ORAS). Four independent OTULIN mouse models reveal that OTULIN deficiency in immune cells results in cell-type-specific effects, ranging from over-production of inflammatory cytokines and autoimmunity due to accumulation of M1-linked polyubiquitin and spontaneous NF-κB activation in myeloid cells to downregulation of M1-polyubiquitin signaling by degradation of LUBAC in B and T cells. Remarkably, treatment with anti-TNF neutralizing antibodies ameliorates inflammation in ORAS patients and rescues mouse phenotypes. Hence, OTULIN is critical for restraining life-threatening spontaneous inflammation and maintaining immune homeostasis.

Original languageEnglish
Pages (from-to)1215-1230.e20
Issue number5
Publication statusPublished - 25 Aug 2016


  • Animals
  • Antibodies, Neutralizing/therapeutic use
  • Autoimmune Diseases/genetics
  • Autoimmunity/genetics
  • B-Lymphocytes/immunology
  • Cytokines/metabolism
  • Deubiquitinating Enzymes/genetics
  • Disease Models, Animal
  • Endopeptidases/genetics
  • Germ-Line Mutation
  • Humans
  • Inflammation/genetics
  • Infliximab/therapeutic use
  • Methionine/metabolism
  • Mice
  • Mice, Mutant Strains
  • Myeloid Cells/immunology
  • Polyubiquitin/metabolism
  • Sequence Deletion
  • Syndrome
  • T-Lymphocytes/immunology
  • Tumor Necrosis Factor-alpha/antagonists & inhibitors


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