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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Published in:	Cell Vol. 166; no. 5; p. 1215
Main Authors:	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
Language:	English
Published:	United States 25.08.2016
Subjects:	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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Abstract	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.
AbstractList	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.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. 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.
Author	Titheradge, Hannah L Marco-Casanova, Paola Komander, David Damgaard, Rune Busk McKenzie, Andrew N J Walker, Jennifer A McHale, Duncan Morgan, Neil V Elliott, Paul R Maher, Eamonn R
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SubjectTerms	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
Title	The Deubiquitinase OTULIN Is an Essential Negative Regulator of Inflammation and Autoimmunity
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