OTULIN limits cell death and inflammation by deubiquitinating LUBAC

• Published in: Nature (London) 2018-07, Vol.559 (7712), p.120-124
• Main Authors: Heger, Klaus, Wickliffe, Katherine E., Ndoja, Ada, Zhang, Juan, Murthy, Aditya, Dugger, Debra L., Maltzman, Allie, de Sousa e Melo, Felipe, Hung, Jeffrey, Zeng, Yi, Verschueren, Erik, Kirkpatrick, Donald S., Vucic, Domagoj, Lee, Wyne P., Roose-Girma, Merone, Newman, Robert J., Warming, Søren, Hsiao, Yi-Chun, Kőműves, László G., Webster, Joshua D., Newton, Kim, Dixit, Vishva M.
• Format: Article
• Language: English
• Subjects: 13/106; 13/2; 13/31; 13/51; 13/95; 631/250/1933; 631/45/607/468; 631/80/458/582; 64/110; 96/21; Animals; Apoptosis; Biochemistry; Biological response modifiers; Bone marrow; Caspase; Caspase 8 - genetics; Caspase 8 - metabolism; Caspase-8; Cell death; Cell Death - genetics; Chemokines; Cytokines; Deactivation; Deubiquitinating Enzymes - genetics; Deubiquitinating Enzymes - metabolism; Embryo; Embryo Loss - genetics; Embryonic development; Embryos; Endopeptidases - genetics; Endopeptidases - metabolism; Endothelial cells; Endothelium; Fibroblasts; Humanities and Social Sciences; Inactivation; Inflammation; Inflammation - enzymology; Inflammation - genetics; Inflammation - metabolism; Interferon; Interferon Type I - biosynthesis; Kinases; Lethality; Letter; Mice; Mice, Inbred C57BL; Mortality; multidisciplinary; Mutation; Necroptosis; Necrosis; Physiological aspects; Physiological research; Protein kinase; Protein kinases; Proteins; Receptor-Interacting Protein Serine-Threonine Kinases - deficiency; Receptor-Interacting Protein Serine-Threonine Kinases - genetics; Receptor-Interacting Protein Serine-Threonine Kinases - metabolism; Regulators; Rodents; Science; Science (multidisciplinary); Small intestine; Stem cells; TNF inhibitors; Tumor necrosis factor; Tumor necrosis factor receptors; Tumor necrosis factor-TNF; Tumors; Ubiquitin; Ubiquitin - chemistry; Ubiquitin - metabolism; Ubiquitination; Ubiquitination - genetics; Weight Loss - genetics
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-018-0256-2

OTULIN (OTU deubiquitinase with linear linkage specificity) removes linear polyubiquitin from proteins that have been modified by LUBAC (linear ubiquitin chain assembly complex) and is critical for preventing auto-inflammatory disease 1 , 2 and embryonic lethality during mouse development 3 . Here we show that OTULIN promotes rather than counteracts LUBAC activity by preventing its auto-ubiquitination with linear polyubiquitin. Thus, knock-in mice that express catalytically inactive OTULIN, either constitutively or selectively in endothelial cells, resembled LUBAC-deficient mice 4 and died midgestation as a result of cell death mediated by TNFR1 (tumour necrosis factor receptor 1) and the kinase activity of RIPK1 (receptor-interacting protein kinase 1). Inactivation of OTULIN in adult mice also caused pro-inflammatory cell death. Accordingly, embryonic lethality and adult auto-inflammation were prevented by the combined loss of cell death mediators: caspase 8 for apoptosis and RIPK3 for necroptosis. Unexpectedly, OTULIN mutant mice that lacked caspase 8 and RIPK3 died in the perinatal period, exhibiting enhanced production of type I interferon that was dependent on RIPK1. Collectively, our results indicate that OTULIN and LUBAC function in a linear pathway, and highlight a previously unrecognized interaction between linear ubiquitination, regulators of cell death, and induction of type I interferon. OTULIN, which removes ubiquitin chains deposited by LUBAC, promotes LUBAC activity by preventing its auto-ubiquitination, thereby supporting normal mouse embryo development and preventing pro-inflammatory cell death in adult mice.