Abstract |
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 disease1,2 and embryonic lethality during mouse development3. 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 mice4 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.
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Authors | Klaus Heger, Katherine E Wickliffe, Ada Ndoja, Juan Zhang, Aditya Murthy, Debra L Dugger, Allie Maltzman, Felipe de Sousa E Melo, Jeffrey Hung, Yi Zeng, Erik Verschueren, Donald S Kirkpatrick, Domagoj Vucic, Wyne P Lee, Merone Roose-Girma, Robert J Newman, Søren Warming, Yi-Chun Hsiao, László G Kőműves, Joshua D Webster, Kim Newton, Vishva M Dixit |
Journal | Nature
(Nature)
Vol. 559
Issue 7712
Pg. 120-124
(07 2018)
ISSN: 1476-4687 [Electronic] England |
PMID | 29950720
(Publication Type: Journal Article)
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Chemical References |
- Interferon Type I
- Ubiquitin
- Receptor-Interacting Protein Serine-Threonine Kinases
- Ripk3 protein, mouse
- Endopeptidases
- gumby protein, mouse
- Deubiquitinating Enzymes
- Casp8 protein, mouse
- Caspase 8
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Topics |
- Animals
- Caspase 8
(genetics, metabolism)
- Cell Death
(genetics)
- Deubiquitinating Enzymes
(genetics, metabolism)
- Embryo Loss
(genetics)
- Endopeptidases
(genetics, metabolism)
- Inflammation
(enzymology, genetics, metabolism)
- Interferon Type I
(biosynthesis)
- Mice
- Mice, Inbred C57BL
- Receptor-Interacting Protein Serine-Threonine Kinases
(deficiency, genetics, metabolism)
- Ubiquitin
(chemistry, metabolism)
- Ubiquitination
(genetics)
- Weight Loss
(genetics)
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