Cells must adapt to changes in their environment to maintain cell, tissue and organismal integrity in the face of mechanical, chemical or microbiological stress. Nuclear factor-κB (NF-κB) is one of the most important transcription factors that controls inducible gene expression as cells attempt to restore homeostasis. It plays critical roles in the immune system, from acute inflammation to the development of secondary lymphoid organs, and also has roles in cell survival, proliferation and differentiation. Given its role in such critical processes, NF-κB signalling must be subject to strict spatiotemporal control to ensure measured and context-specific cellular responses. Indeed, deregulation of NF-κB signalling can result in debilitating and even lethal inflammation and also underpins some forms of cancer. In this review, we describe the homeostatic feedback mechanisms that limit and ‘re-set’ inducible activation of NF-κB. We first describe the key components of the signalling pathways leading to activation of NF-κB, including the prominent role of protein phosphorylation and protein ubiquitylation, before briefly introducing the key features of feedback control mechanisms. We then describe the array of negative feedback loops targeting different components of the NF-κB signalling cascade including controls at the receptor level, post-receptor signalosome complexes, direct regulation of the critical ‘inhibitor of κB kinases’ (IKKs) and inhibitory feedforward regulation of NF-κB-dependent transcriptional responses. We also review post-transcriptional feedback controls affecting RNA stability and translation. Finally, we describe the deregulation of these feedback controls in human disease and consider how feedback may be a challenge to the efficacy of inhibitors.

中文翻译：

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NF-κB 信号在健康和疾病中的抑制反馈控制

细胞必须适应环境的变化，以在面临机械、化学或微生物压力时保持细胞、组织和机体的完整性。核因子-κB (NF-κB) 是最重要的转录因子之一，可在细胞试图恢复稳态时控制诱导基因表达。它在免疫系统中发挥着关键作用，从急性炎症到次级淋巴器官的发育，并且还在细胞存活、增殖和分化中发挥作用。鉴于其在此类关键过程中的作用，NF-κB 信号必须受到严格的时空控制，以确保测量和特定于上下文的细胞反应。事实上，NF-κB 信号传导的失调会导致使人虚弱甚至致命的炎症，并且还会导致某些形式的癌症。在这次审查中，我们描述了限制和“重置”NF-κB 诱导激活的稳态反馈机制。我们首先描述导致 NF-κB 激活的信号通路的关键组成部分，包括蛋白质磷酸化和蛋白质泛素化的突出作用，然后简要介绍反馈控制机制的关键特征。然后，我们描述了一系列针对 NF-κB 信号级联不同成分的负反馈回路，包括受体水平的控制、受体后信号小体复合物、关键“κB 激酶抑制剂”（IKK）的直接调节和抑制性前馈调节NF-κB 依赖的转录反应。我们还回顾了影响 RNA 稳定性和翻译的转录后反馈控制。最后，