The canonical NF-κB activation pathway. Binding of TNFα trimers to TNFR receptors initiates the canonical signaling pathway by activating the upstream kinase IKK. IKK phosphorylates the IκB inhibitor that is bound to NF-κB in the resting state. This targets IκB proteins for the ubiquitin-proteasome system, which leads to IκB destruction by the 26S proteasome and release of NF-κB. Free NF-κB enters the nucleus and activates gene expression of many target genes and induces negative feedback regulation by synthesizing IκB and A20. IκB proteins inhibit NF-κB activity by sequestering NF-κB from the nucleus to form an inner feedback loop, while A20 attenuates stimulus induced IKK kinase activation further upstream in an outer negative feedback loop.