Kupka Sebastian, Reichert Matthias, Draber Peter, Walczak Henning
Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, London, UK.
FEBS J. 2016 Jul;283(14):2626-39. doi: 10.1111/febs.13644. Epub 2016 Jan 24.
Tumor necrosis factor (TNF) is a potent cytokine known for its involvement in inflammation, repression of tumorigenesis and activation of immune cells. Consequently, accurate regulation of the TNF signaling pathway is crucial for preventing the potent noxious effects of TNF. These pathological conditions include chronic inflammation, septic shock, cachexia and cancer. The TNF signaling cascade utilizes a complex network of post-translational modifications to control the cellular response following its activation. Next to phosphorylation, the ubiquitination of signaling complex components is probably the most important modification. This process is mediated by a specialist class of enzymes, the ubiquitin ligases. Equally important is the class of dedicated ubiquitin-specific proteases, the deubiquitinases. Together with ubiquitin binding proteins, this ubiquitination-deubiquitination system enables the dynamics of signaling complexes. In TNF signaling, these dynamics translate into the precise regulation of the induction of gene activation or cell death. Here, we review and discuss current knowledge of TNF signaling regulation by the ubiquitin system.
肿瘤坏死因子（TNF）是一种强效细胞因子，因其参与炎症反应、抑制肿瘤发生以及激活免疫细胞而闻名。因此，精确调控TNF信号通路对于预防TNF的有害作用至关重要。这些病理状况包括慢性炎症、脓毒症休克、恶病质和癌症。TNF信号级联利用一个复杂的翻译后修饰网络来控制其激活后的细胞反应。除了磷酸化，信号复合物成分的泛素化可能是最重要的修饰。这个过程由一类特殊的酶——泛素连接酶介导。同样重要的是一类专门的泛素特异性蛋白酶——去泛素化酶。与泛素结合蛋白一起，这个泛素化-去泛素化系统实现了信号复合物的动态变化。在TNF信号传导中，这些动态变化转化为对基因激活或细胞死亡诱导的精确调控。在此，我们综述并讨论泛素系统对TNF信号传导调控的当前知识。
