Activation of NF-kappaB transcription factors by receptors of the innate or adaptive immune system is essential for host defense. However, after danger is eliminated, NF-kappaB signaling needs to be tightly downregulated for the maintenance of tissue homeostasis. This review highlights key negative regulatory principles that affect the amount, localization or conformational properties of NF-kappaB-activating proteins to attenuate the NF-kappaB response. These mechanisms are needed to prevent inflammation, autoimmune disease and oncogenesis.
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