Department of Disease Biology, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, 2200 Copenhagen, Denmark.
Mol Cell. 2012 Jun 29;46(6):746-58. doi: 10.1016/j.molcel.2012.04.014. Epub 2012 May 17.
Nucleotide-binding and oligomerization domain (NOD)-like receptors constitute a first line of defense against invading bacteria. X-linked Inhibitor of Apoptosis (XIAP) is implicated in the control of bacterial infections, and mutations in XIAP are causally linked to immunodeficiency in X-linked lymphoproliferative syndrome type-2 (XLP-2). Here, we demonstrate that the RING domain of XIAP is essential for NOD2 signaling and that XIAP contributes to exacerbation of inflammation-induced hepatitis in experimental mice. We find that XIAP ubiquitylates RIPK2 and recruits the linear ubiquitin chain assembly complex (LUBAC) to NOD2. We further show that LUBAC activity is required for efficient NF-κB activation and secretion of proinflammatory cytokines after NOD2 stimulation. Remarkably, XLP-2-derived XIAP variants have impaired ubiquitin ligase activity, fail to ubiquitylate RIPK2, and cannot facilitate NOD2 signaling. We conclude that XIAP and LUBAC constitute essential ubiquitin ligases in NOD2-mediated inflammatory signaling and propose that deregulation of NOD2 signaling contributes to XLP-2 pathogenesis.
核苷酸结合寡聚化结构域（NOD）样受体是抵御入侵细菌的第一道防线。凋亡抑制因子（XIAP）参与了细菌感染的控制，而 XIAP 的突变与 X 连锁淋巴组织增生综合征 2 型（XLP-2）中的免疫缺陷有关。在这里，我们证明了 XIAP 的 RING 结构域对于 NOD2 信号转导是必不可少的，并且 XIAP 有助于实验小鼠中炎症诱导的肝炎的恶化。我们发现 XIAP 泛素化 RIPK2 并招募线性泛素链组装复合物（LUBAC）到 NOD2。我们进一步表明，在 NOD2 刺激后，LUBAC 活性对于 NF-κB 的有效激活和促炎细胞因子的分泌是必需的。值得注意的是，XLP-2 衍生的 XIAP 变体具有受损的泛素连接酶活性，不能泛素化 RIPK2，并且不能促进 NOD2 信号转导。我们得出结论，XIAP 和 LUBAC 构成了 NOD2 介导的炎症信号转导中必需的泛素连接酶，并提出 NOD2 信号转导的失调导致了 XLP-2 的发病机制。
