Signaling to NF-kappaB: regulation by ubiquitination

Abstract

The NF-kappaB pathway is a ubiquitous stress response that activates the NF-kappaB family of transcription factors. Antigen receptors, receptors of the innate immune system, and certain intracellular stressors are potent activators of this pathway. The transcriptional program that is activated is both antiapoptotic and highly proinflammatory. Indeed, any compromise in engagement of the pathway results in immunodeficiency, whereas constitutive activation generates a sustained inflammatory response that may promote malignancy. As such, NF-kappaB activation is under tight regulation by a number of post-translational modifications, including phosphorylation and ubiquitination. This article attempts to synthesize our current knowledge regarding the regulation of NF-kappaB signaling by ubiquitination, specifically highlighting the biochemical basis for both positive and negative feedback loops that function in unison to generate coordinated signals that are essential for the viability of metazoan animals.

Figure 1.

Enzymes and reactions of the ubiquitin/proteasome system.

Figure 2.

TNFR1 and TLR4 signaling pathways. Lys-48-linked ubiquitin chains are shown in red, and Lys-63-linked ubiquitin chains are shown in green. See text for additional details.

Figure 3.

CD40 signaling pathways. Lys-48-linked ubiquitin chains are shown in red, and Lys-63-linked ubiquitin chains are shown in green. See text for additional details.

Figure 4.

TCR signaling pathways. Lys-48-linked ubiquitin chains are shown in red, and Lys-63-linked ubiquitin chains are shown in green. See text for additional details.

Figure 5.

NF-κB activation by intracellular receptors. Lys-48-linked ubiquitin chains are shown in red, Lys-63-linked ubiquitin chains are shown in green, SUMOylation is indicated by blue circles, and monoubiquitination is indicated by green circles. See text for additional details.