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

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...

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Veröffentlicht in:Cell Jg. 166; H. 5; S. 1215
Hauptverfasser: Damgaard, Rune Busk, Walker, Jennifer A, Marco-Casanova, Paola, Morgan, Neil V, Titheradge, Hannah L, Elliott, Paul R, McHale, Duncan, Maher, Eamonn R, McKenzie, Andrew N J, Komander, David
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 25.08.2016
Schlagworte:
Animals
Antibodies, Neutralizing - therapeutic use
Autoimmune Diseases - genetics
Autoimmune Diseases - immunology
Autoimmune Diseases - therapy
Autoimmunity - genetics
B-Lymphocytes - immunology
Cytokines - metabolism
Deubiquitinating Enzymes - genetics
Deubiquitinating Enzymes - metabolism
Disease Models, Animal
Endopeptidases - genetics
Endopeptidases - metabolism
Germ-Line Mutation
Humans
Inflammation - genetics
Inflammation - immunology
Inflammation - therapy
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
ISSN:1097-4172, 1097-4172
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Zusammenfassung: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.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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ISSN:1097-4172
1097-4172
DOI:10.1016/j.cell.2016.07.019