Anatomy of a negative feedback loop: the case of I?B?.

ABSTRACT: The magnitude, duration and oscillation of cellular signalling pathway responses are often limited by negative feedback loops, defined as an 'activator-induced inhibitor' regulatory motif. Within the NF?B signalling pathway, a key negative feedback regulator is I?B?. We show here that, contrary to current understanding, NF?B-inducible expression is not sufficient for providing effective negative feedback. We then employ computational simulations of NF?B signalling to identify I?B? molecular properties that are critical for proper negative feedback control and test the resulting predictions in biochemical and single-cell live-imaging studies. We identified nuclear import and nuclear export of I?B? and the I?B?-NF?B complex, as well as the free I?B? half-life, as key determinants of post-induction repression of NF?B and the potential for subsequent reactivation. Our work emphasizes that negative feedback is an emergent systems property determined by multiple molecular and biophysical properties in addition to the required 'activator-induced inhibitor' relationship.

SUBMITTER: Fagerlund R 

PROVIDER: S-EPMC4614452 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature