Figure 1.

Main signaling pathways of NF-κB activation. In the classical pathway, the IKK complex is activated in response to different molecules such as the pro-inflammatory cytokines TNF-α and IL-1β, or lipopolysaccharides (LPS), followed by phosphorylation and degradation of the NF-κB inhibitor IκBα, the release of the dimers of NF-κB and their translocation into the nucleus, where they induce the transcription of multiple NF-κB target genes. The activation of NF-κB through the alternative pathway depends on IKKα homodimers. It is activated in response to cytokines such as lymphotoxin β (LTβ), the B-cell activating factor (BAFF), or the CD40 ligand. NIK kinase phosphorylates and activates IKKα leading to the processing of p100 and the formation of the heterodimer RELB/p52, which enters the nucleus and regulates the transcription of target genes. In the atypical pathway of NF-κB activation described in keratinocytes, in response to TPA or UV light, CYLD translocates from the cytoplasm to the perinuclear region where it deubiquitinates BCL3 and prevents nuclear accumulation of p50/BCL3 or p52/BCL3, thereby inhibiting the activation of NF-kB.