Theoretical analyses predict A20 regulates period of NF-kB oscillation

TL;DR

This paper presents a theoretical model of NF-kB oscillations highlighting the role of A20 in regulating oscillation period and damping, revealing new insights into feedback mechanisms controlling immune response dynamics.

Contribution

The study introduces a novel model focusing on A20's role in NF-kB oscillation regulation, demonstrating its impact on period control and damping mechanisms.

Findings

A20 dampens NF-kB oscillations through a distinct mechanism.

A20 controls the oscillation period of nuclear NF-kB.

Adjusting A20 levels can change oscillation period by up to twofold.

Abstract

The nuclear-cytoplasmic shuttling of NF-kB is characterized by damped oscillations of the nuclear concentration with a time period of around 1-2 hours. The NF-kB network contains several feedback loops modulating the overall response of NF-kB activity. While IkBa is known to drive and IkBe is known to dampen the oscillations, the precise role of A20 negative feedback remains to be elucidated. Here we propose a model of the NF-kB system focusing on three negative feedback loops (IkBa, IkBe and A20) which capture the experimentally observed responses in wild-type and knockout cells. We find that A20, like IkBe, efficiently dampens the oscillations albeit 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-kB. The design based on three nested feedback loops allows independent control of period and amplitude decay in the oscillatory response. Based on these results we predict that adjusting the expression level of A20, e.g. by siRNA, the period can be changed by up to a factor 2.