OTULIN limits cell death and inflammation by deubiquitinating LUBAC

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 () and Vishva M. Dixit ()
Additional contact information
Klaus Heger: Genentech
Katherine E. Wickliffe: Genentech
Ada Ndoja: Genentech
Juan Zhang: Genentech
Aditya Murthy: Genentech
Debra L. Dugger: Genentech
Allie Maltzman: Genentech
Felipe de Sousa e Melo: Genentech
Jeffrey Hung: Genentech
Yi Zeng: Proteomics and Lipidomics, Genentech
Erik Verschueren: Proteomics and Lipidomics, Genentech
Donald S. Kirkpatrick: Proteomics and Lipidomics, Genentech
Domagoj Vucic: Genentech
Wyne P. Lee: Genentech
Merone Roose-Girma: Genentech
Robert J. Newman: Genentech
Søren Warming: Genentech
Yi-Chun Hsiao: Genentech
László G. Kőműves: Genentech
Joshua D. Webster: Genentech
Kim Newton: Genentech
Vishva M. Dixit: Genentech

Nature, 2018, vol. 559, issue 7712, 120-124

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41586-018-0256-2

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