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Cell. 2016 Aug 25;166(5):1215-1230.e20. doi: 10.1016/j.cell.2016.07.019. Epub 2016 Aug 11.

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

Author information

1
Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.
2
Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.
3
Department of Clinical Genetics, Birmingham Women's NHS Foundation Trust, Birmingham B15 2TG, UK; Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham B15 2TT, UK.
4
New Medicines, UCB Pharma, Slough SL1 3WE, UK.
5
Department of Medical Genetics, University of Cambridge and Cambridge NIHR Biomedical Research Centre, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK. Electronic address: erm1000@medschl.cam.ac.uk.
6
Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK. Electronic address: anm@mrc-lmb.cam.ac.uk.
7
Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK. Electronic address: dk@mrc-lmb.cam.ac.uk.

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.

PMID:
27523608
PMCID:
PMC5002269
DOI:
10.1016/j.cell.2016.07.019
[Indexed for MEDLINE]
Free PMC Article

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