The linear ubiquitin chain assembly complex regulates TRAIL-induced gene activation and cell death.
The linear ubiquitin chain assembly complex regulates TRAIL-induced gene activation and cell death.
复制标题
DOI：
10.15252/embj.201695699
复制
发表时间：
2017-05-02
期刊：
影响因子：
--
通讯作者：
Walczak H
中科院分区：
文献类型：
--
作者：
Lafont E;Kantari-Mimoun C;Draber P;De Miguel D;Hartwig T;Reichert M;Kupka S;Shimizu Y;Taraborrelli L;Spit M;Sprick MR;Walczak H
线性泛素链组装复合体（LUBAC）是唯一已知的E3泛素连接酶，它可以催化从头生成线性泛素键。LUBAC是多种免疫受体信号通路的重要组成部分。在这里，我们发现LUBAC形成了TRAIL‐R相关复合体I以及细胞质TRAIL‐诱导复合体II的一部分。在这两种复合物中，HOIP限制了caspase‐8的活性，因此，在以caspase‐8依赖的方式被切割的同时，也限制了细胞凋亡。然而，通过限制RIPK1/RIPK3/MLKL复合物的形成，LUBAC也限制TRAIL诱导的坏死坏死。我们发现RIPK1和caspase‐8是TRAIL刺激后LUBAC的线性泛素化靶标。与其在预防TRAIL诱导的RIPK1非依赖性细胞凋亡中的作用相反，HOIP的存在（而不是其活性）是预防坏死性坏死所必需的。通过促进IKK复合体向复合体I的募集，LUBAC还促进TRAIL诱导的NF - κB活化，从而促进FADD、caspase - 8和cIAP1/2下游细胞因子的产生。因此，LUBAC控制复合体I和II的TRAIL信号转导结果，这两个平台都触发细胞死亡和基因激活。
The linear ubiquitin chain assembly complex (LUBAC) is the only known E3 ubiquitin ligase which catalyses the generation of linear ubiquitin linkages de novo. LUBAC is a crucial component of various immune receptor signalling pathways. Here, we show that LUBAC forms part of the TRAIL‐R‐associated complex I as well as of the cytoplasmic TRAIL‐induced complex II. In both of these complexes, HOIP limits caspase‐8 activity and, consequently, apoptosis whilst being itself cleaved in a caspase‐8‐dependent manner. Yet, by limiting the formation of a RIPK1/RIPK3/MLKL‐containing complex, LUBAC also restricts TRAIL‐induced necroptosis. We identify RIPK1 and caspase‐8 as linearly ubiquitinated targets of LUBAC following TRAIL stimulation. Contrary to its role in preventing TRAIL‐induced RIPK1‐independent apoptosis, HOIP presence, but not its activity, is required for preventing necroptosis. By promoting recruitment of the IKK complex to complex I, LUBAC also promotes TRAIL‐induced activation of NF‐κB and, consequently, the production of cytokines, downstream of FADD, caspase‐8 and cIAP1/2. Hence, LUBAC controls the TRAIL signalling outcome from complex I and II, two platforms which both trigger cell death and gene activation.