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The DeubiquitinaseOTULIN Is anEssential NegativeRegulator ofInflammation andAutoimmunity Rune Busk DamgaardJennifer A. WalkerPaola Marco‐Casanova2016 год

The Deubiquitinase OTULIN Is an Essential Negative Regulator of Inflammation and Autoimmunity
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Аннотация: Highlights•Mutation of OTULIN causes OTULIN-related autoinflammatory syndrome (ORAS) in humans•Anti-TNF treatment reverses inflammation in ORAS patient and OTULIN-deficient mice•OTULIN deficiency deregulates M1-polyUb signaling and causes sterile inflammation•Loss of OTULIN has cell-type-specific effects on LUBAC abundance and signalingSummaryMethionine-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.Graphical abstract
Год издания: 2016
Авторы: Rune Busk Damgaard, Jennifer A. Walker, Paola Marco‐Casanova, Neil V. Morgan, Hannah Titheradge, P.R. Elliott, Duncan McHale, Eamonn R. Maher, Andrew N. J. McKenzie, David Komander
Издательство: Cell Press
Источник: Cell
Ключевые слова: Immune Cell Function and Interaction, Inflammasome and immune disorders, Autoimmune and Inflammatory Disorders Research
Другие ссылки: Cell (HTML)
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