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The nuclear-cytoplasmic shuttling of NF-kB is characterized by dampedoscillations of the nuclear concentration with a time period of around 1-2hours. The NF-kB network contains several feedback loops modulating the overallresponse of NF-kB activity. While IkBa is known to drive and IkBe is known todampen the oscillations, the precise role of A20 negative feedback remains tobe elucidated. Here we propose a model of the NF-kB system focusing on threenegative feedback loops (IkBa, IkBe and A20) which capture the experimentallyobserved responses in wild-type and knockout cells. We find that A20, likeIkBe, efficiently dampens the oscillations albeit through a distinct mechanism.In addition, however, we have discovered a new functional role of A20 by whichit controls the oscillation period of nuclear NF-kB. The design based on threenested feedback loops allows independent control of period and amplitude decayin the oscillatory response. Based on these results we predict that adjustingthe expression level of A20, e.g. by siRNA, the period can be changed by up toa factor 2.

Theoretical analyses predict A20 regulates period of NF-kB oscillation