Tumour Immunology Unit, Division of Immunology and Inflammation, Department of Medicine, Imperial College London, London, UK.
Immunol Rev. 2011 Nov;244(1):9-28. doi: 10.1111/j.1600-065X.2011.01066.x.
Tumor necrosis factor (TNF) is crucial for innate immunity, but deregulated TNF signaling also plays an eminent role in the pathogenesis of many chronic inflammatory diseases and cancer-related inflammation. The signals that mediate both the beneficial and the harmful effects of TNF are initiated when TNF binds to its receptors on the surface of target cells. TNF receptor 1 (TNFR1) is ubiquitously expressed, whereas TNFR2 is mainly expressed on lymphocytes and endothelial cells. This review focuses on the molecular and physiological consequences of the interaction of TNF with TNFR1. The different outcomes of TNF signaling originate at the apical signaling complex that forms when TNF binds to TNFR1, the TNFR1 signaling complex (TNF-RSC). By integrating recently gained insight on the functional importance of the presence of different types of ubiquitination in the TNF-RSC, including linear ubiquitin linkages generated by the linear ubiquitin chain assembly complex (LUBAC), with the equally recent elucidation of the mode in which ubiquitin-binding domains interact with specific di-ubiquitin linkages, this review develops a new concept for the way the concerted action of different ubiquitination events enables the TNF-RSC to generate its signaling output in a spatio-temporally controlled manner. Finally, it will be explained how these new findings and the emerging concept of differential ubiquitination governing the TNF-RSC may impact future research on the molecular mechanism of TNF signaling and the function of this cytokine in normal physiology, chronic inflammation, and cancer.
肿瘤坏死因子（TNF）对于先天免疫至关重要，但是，TNF 信号的失调也在许多慢性炎症性疾病和癌症相关炎症的发病机制中起着重要作用。当 TNF 与其靶细胞表面的受体结合时，介导 TNF 的有益和有害作用的信号就会被启动。TNF 受体 1（TNFR1）广泛表达，而 TNFR2 主要表达于淋巴细胞和内皮细胞。这篇综述重点介绍了 TNF 与 TNFR1 相互作用的分子和生理后果。TNF 信号的不同结果源于 TNF 与 TNFR1 结合时形成的顶端信号复合物，即 TNFR1 信号复合物（TNF-RSC）。通过整合最近获得的关于 TNF-RSC 中不同类型泛素化的功能重要性的见解，包括线性泛素链组装复合物（LUBAC）产生的线性泛素连接，以及泛素结合结构域与特定二泛素连接相互作用的模式，这篇综述提出了一个新概念，即不同泛素化事件的协同作用如何使 TNF-RSC 以时空控制的方式产生其信号输出。最后，将解释这些新发现和新兴的 TNF-RSC 差异化泛素化概念如何影响 TNF 信号分子机制以及该细胞因子在正常生理学、慢性炎症和癌症中的功能的未来研究。
