淋巴毒素 β 受体 (LTβR) 是 TNF 受体超家族 (TNFR-SF) 的成员，对于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癌发生。然而，我们目前缺乏对 LTβR 信号传导的详细了解。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) 的一个先前未被识别且功能上至关重要的组成部分。从机制上讲，LUBAC 生成的线性泛素链能够将 NEMO、OPTN 和 A20 招募到 LTβR-SC，在那里它们协调作用，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，而在 LTβR 信号传导中，LUBAC 通过启用规范和干扰非规范 NF-κB 激活来实现炎症信号传导。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 高表达与预后不良相关，这为 LUBAC 介导的炎症 LTβR 信号传导提供了临床相关性。© 2024。作者。

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.© 2024. The Author(s).