Journal
CELL
Volume 166, Issue 5, Pages 1215-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2016.07.019
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Funding
- Medical Research Council [U105192732, U105178805]
- European Research Council [309756]
- Lister Institute for Preventive Medicine
- EMBO Young Investigator Program
- Marie-Sklodowska Curie Individual Fellowship from European Commission [MC-IF-654019]
- Corpus Christi College Cambridge
- Wellcome Trust [100963/Z/13/Z]
- WellChild
- UCB
- Medical Research Council [MC_U105192732, MC_U105178805] Funding Source: researchfish
- Wellcome Trust [100963/Z/13/Z] Funding Source: researchfish
- MRC [MC_U105192732, MC_U105178805] Funding Source: UKRI
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Methionine-1 (M1)-linked ubiquitin chains regulate the activity of NF-kappa B, 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-kB 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.
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