| First Author | Damgaard RB | Year | 2016 |
| Journal | Cell | Volume | 166 |
| Issue | 5 | Pages | 1215-1230.e20 |
| PubMed ID | 27523608 | Mgi Jnum | J:236075 |
| Mgi Id | MGI:5804663 | Doi | 10.1016/j.cell.2016.07.019 |
| Citation | Damgaard RB, et al. (2016) The Deubiquitinase OTULIN Is an Essential Negative Regulator of Inflammation and Autoimmunity. Cell 166(5):1215-1230.e20 |
| abstractText | Methionine-1 (M1)-linked ubiquitin chains regulate the activity of NF-kappaB, 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-kappaB 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. |
