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.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.

中文翻译：

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OTULIN 通过去泛素化 LUBAC 限制细胞死亡和炎症

OTULIN（具有线性连接特异性的 OTU 脱泛素酶）从已被 LUBAC（线性泛素链组装复合物）修饰的蛋白质中去除线性多聚泛素，并且对于预防小鼠发育过程中的自身炎症疾病 1,2 和胚胎致死至关重要 3。在这里，我们表明 OTULIN 通过阻止其与线性多聚泛素的自动泛素化来促进而不是抵消 LUBAC 活性。因此，在内皮细胞中组成性或选择性表达催化失活 OTULIN 的敲入小鼠类似于 LUBAC 缺陷小鼠 4，并且由于 TNFR1（肿瘤坏死因子受体 1）和 RIPK1 的激酶活性介导的细胞死亡而在妊娠中期死亡（受体相互作用蛋白激酶 1）。成年小鼠中 OTULIN 的失活也会导致促炎细胞死亡。因此，细胞死亡介质（用于细胞凋亡的半胱天冬酶 8 和用于坏死性凋亡的 RIPK3）的联合损失阻止了胚胎致死率和成人自身炎症。出乎意料的是，缺乏 caspase 8 和 RIPK3 的 OTULIN 突变小鼠在围产期死亡，表现出依赖 RIPK1 的 I 型干扰素的产生增加。总的来说，我们的结果表明 OTULIN 和 LUBAC 在线性途径中起作用，并突出了线性泛素化、细胞死亡调节剂和 I 型干扰素诱导之间以前未被认识的相互作用。 OTULIN 去除了 LUBAC 沉积的泛素链，促进了 LUBAC 活性通过阻止其自身泛素化，从而支持正常的小鼠胚胎发育并防止成年小鼠的促炎细胞死亡。