A20 Negative Feedback Regulates Period of NF-KB Oscillations

The nuclear-cytoplasmic shuttling of NF-κB is characterized by damped oscillations of the nuclear concentration with a time period of around 1.5 hours. The NF-κB network contains several feedback loops modulating the overall response of NF-κB activity. While IκBα is known to drive and IκBe is know to dampen the oscillations the precise role of A20 negative feedback remains to be elucidated. Here we propose a reduced model of the NF-κB system focusing on three negative feedback loops (IκBα, IκBe and A20) which capture the experimentally observed responses in wild-type and knockout cells. We find that A20, like IκBe, efficiently dampens the oscillations although through a distinct mechanism. In addition however we have discovered a new functional role of A20 by which it controls the oscillation period of nuclear NF-κB. The design based on three nested feedback loops allows an exploration of different oscillatory responses where both period and amplitude decay can be modified. Based on these results we predict that adjusting the expression level of A20, by e.g. siRNA, the period can be changed from 1h to 3h.