Lymphotoxin β receptor (LTβR), a member of the TNF receptor superfamily (TNFR-SF), is essential for development and maturation of lymphoid organs. In addition, LTβR activation promotes carcinogenesis by inducing a proinflammatory secretome. Yet, we currently lack a detailed understanding of LTβR signaling. In this study we discovered the linear ubiquitin chain assembly complex (LUBAC) as a previously unrecognized and functionally crucial component of the native LTβR signaling complex (LTβR-SC). Mechanistically, LUBAC-generated linear ubiquitin chains enable recruitment of NEMO, OPTN and A20 to the LTβR-SC, where they act coordinately to regulate the balance between canonical and non-canonical NF-κB pathways. Thus, different from death receptor signaling, where LUBAC prevents inflammation through inhibition of cell death, in LTβR signaling LUBAC is required for inflammatory signaling by enabling canonical and interfering with non-canonical NF-κB activation. This results in a LUBAC-dependent LTβR-driven inflammatory, protumorigenic secretome. Intriguingly, in liver cancer patients with high LTβR expression, high expression of LUBAC correlates with poor prognosis, providing clinical relevance for LUBAC-mediated inflammatory LTβR signaling.

淋巴毒素β受体 （LTβR） 是 TNF 受体超家族 （TNFR-SF） 的成员，对淋巴器官的发育和成熟至关重要。此外，LTβR 激活通过诱导促炎分泌组促进致癌。然而，我们目前缺乏对 LTβR 信号传导的详细理解。在这项研究中，我们发现线性泛素链组装复合物 （LUBAC） 是天然 LTβR 信号复合物 （LTβR-SC） 以前未被识别且功能关键的组成部分。从机制上讲，LUBAC 产生的线性泛素链能够将 NEMO、OPTN 和 A20 募集到 LTβR-SC，在那里它们协调作用以调节经典和非经典 NF-κB 通路之间的平衡。因此，与死亡受体信号传导不同，LUBAC 通过抑制细胞死亡来预防炎症，在 LTβR 信号传导中，LUBAC 通过启用经典和干扰非经典 NF-κB 激活来成为炎症信号传导所必需的。这导致 LUBAC 依赖性 LTβR 驱动的炎症、促肿瘤分泌组。有趣的是，在 LTβR 高表达的肝癌患者中，LUBAC 的高表达与不良预后相关，为 LUBAC 介导的炎性 LTβR 信号传导提供了临床相关性。