Immune differentiation regulator p100 tunes NF-κB responses to TNF

Summary Stringent regulation of TNF signaling prevents aberrant inflammation. TNF engages the canonical NF-κB pathway for activating the RelA:p50 heterodimer, which mediates specific expressions of pro-inflammatory and immune response genes. Importantly, the NF-κB system discriminates between time-varied TNF inputs. Negative feedback regulators of the canonical pathway, including IκBα, are thought to ensure transient RelA:p50 responses to brief TNF stimulations. The noncanonical NF-κB pathway controls a separate RelB activity associated with immune differentiation. In a systems modeling approach, we uncovered an unexpected role of p100, a constituent of the noncanonical pathway, in TNF signaling. Brief TNF stimulation of p100-deficient cells produced an additional late NF-κB activity consisted of the RelB:p50 heterodimer, which distorted the TNF-induced gene-expression program. Periodic TNF pulses augmented this RelB:p50 activity, which was reinforced by NF-κB-dependent RelB synthesis. In sum, the NF-κB system seems to engage distantly related molecules for enforcing dynamical and gene controls of immune-activating TNF signaling.