Suppression of LUBAC-mediated linear ubiquitination by a specific interaction between LUBAC and the deubiquitinases CYLD and OTULIN
Suppression of LUBAC-mediated linear ubiquitination by a specific interaction between LUBAC and the deubiquitinases CYLD and OTULIN
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DOI：
10.1111/gtc.12128
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发表时间：
2014-03-01
期刊：
影响因子：
2.1
通讯作者：
Iwai, Kazuhiro
中科院分区：
文献类型：
--
作者：
Takiuchi, Tsuyoshi;Nakagawa, Tomoko;Iwai, Kazuhiro
由线性泛素链组装复合物（LUBAC）产生的线性泛素链在NF-κ B活化中起重要作用。然而，LUBAC对线性泛素链生成的调节还没有很好的表征。在这里，我们确定了两种去泛素化酶（DUB），卵巢肿瘤DUB与线性连接特异性（OTULIN/Gumby/FAM 105 B）和圆柱瘤病（CYLD），可以切割线性多聚泛素链，并通过N-末端PNGase/乌巴或HOIP（LUBAC的催化亚基）的UBX（PUB）结构域与LUBAC相互作用。HOIP甚至在未刺激的细胞中与CYLD和OTULIN两者相互作用。CYLD和OTULIN与HOIP的相互作用协同抑制LUBAC介导的线性聚泛素化和NF-κ B活化。此外，将不能结合任一去泛素化酶的HOIP突变体引入HOIP缺失细胞增强了TNF-α刺激对NF-κ B的激活。因此，这两种去泛素化酶和LUBAC泛素连接酶之间的相互作用涉及通过微调LUBAC线性泛素链的产生来控制TNF-α诱导的细胞中NF-κ B活化的程度。HOIP与OTULIN的相互作用还涉及OTULIN抑制LUBAC激活的经典Wnt信号传导途径。我们的观察提供了分子的连接酶-去泛素化酶的相互作用的作用，在调节分子的线性泛素结合所产生的事件的见解。
Linear ubiquitin chains generated by the linear ubiquitin chain assembly complex (LUBAC) play an important role in NF-kappa B activation. However, the regulation of linear ubiquitin chain generation by LUBAC is not well characterized. Here, we identified two deubiquitinating enzymes (DUBs), ovarian tumor DUB with linear linkage specificity (OTULIN/Gumby/FAM105B) and cylindromatosis (CYLD) that can cleave linear polyubiquitin chains and interact with LUBAC via the N-terminal PNGase/UBA or UBX (PUB) domain of HOIP, a catalytic subunit of LUBAC. HOIP interacts with both CYLD and OTULIN even in unstimulated cells. The interaction of CYLD and OTULIN with HOIP synergistically suppresses LUBAC-mediated linear polyubiquitination and NF-kappa B activation. Moreover, introduction of a HOIP mutant unable to bind either deubiquitinase into HOIP-null cells augments the activation of NF-kappa B by TNF-alpha stimulation. Thus, the interactions between these two deubiquitinases and the LUBAC ubiquitin ligase are involved in controlling the extent of TNF-alpha-induced NF-kappa B activation in cells by fine-tuning the generation of linear ubiquitin chains by LUBAC. The interaction of HOIP with OTULIN is also involved in OTULIN suppressing the canonical Wnt signaling pathway activation by LUBAC. Our observations provide molecular insights into the roles of ligase-deubiquitinase interactions in regulating molecular events resulting from linear ubiquitin conjugation.