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bioRxiv · 10.1101/414425

Immune differentiation regulator p100 tunes NF-κB responses to TNF

Chatterjee, B.·Roy, P.·Sarkar, U. A.·Ratra, Y.·Chawla, M.·Gomes, J.·Basak, S.
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Abstract

Stringent regulation of TNF signaling prevents aberrant inflammation. TNF engages the canonical NF-{kappa}B pathway for activating the RelA:p50 heterodimer, which mediates specific expressions of pro-inflammatory and immune response genes. Importantly, the NF-{kappa}B system discriminates between time-varied TNF inputs. Negative feedback regulators of the canonical pathway, including I{kappa}B, are thought to ensure transient RelA:p50 responses to brief TNF stimulations. The noncanonical NF-{kappa}B 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-{kappa}B 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-{kappa}B-dependent RelB synthesis. In sum, the NF-{kappa}B system seems to engage distantly related molecules for enforcing dynamical and gene controls of immune-activating TNF signaling.

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Chatterjee, B., Roy, P., Sarkar, U. A., Ratra, Y., Chawla, M., Gomes, J., Basak, S.. 2018-09-12. Immune differentiation regulator p100 tunes NF-κB responses to TNF. https://doi.org/10.1101/414425

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