| First Author | Heger K | Year | 2018 |
| Journal | Nature | Volume | 559 |
| Issue | 7712 | Pages | 120-124 |
| PubMed ID | 29950720 | Mgi Jnum | J:264084 |
| Mgi Id | MGI:6192867 | Doi | 10.1038/s41586-018-0256-2 |
| Citation | Heger K, et al. (2018) OTULIN limits cell death and inflammation by deubiquitinating LUBAC. Nature 559(7712):120-124 |
| abstractText | 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. |
