Fagerlund Riku, Behar Marcelo, Fortmann Karen T, Lin Y Eason, Vargas Jesse D, Hoffmann Alexander
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA.
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095, USA Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, CA 90095, USA.
J R Soc Interface. 2015 Sep 6;12(110):0262. doi: 10.1098/rsif.2015.0262.
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 NFκB signalling pathway, a key negative feedback regulator is IκBα. We show here that, contrary to current understanding, NFκB-inducible expression is not sufficient for providing effective negative feedback. We then employ computational simulations of NFκB signalling to identify IκBα 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 IκBα and the IκBα-NFκB complex, as well as the free IκBα half-life, as key determinants of post-induction repression of NFκB 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.
细胞信号通路反应的幅度、持续时间和振荡通常受到负反馈回路的限制，负反馈回路被定义为一种“激活剂诱导抑制剂”调节基序。在NFκB信号通路中，一个关键的负反馈调节因子是IκBα。我们在此表明，与当前的认识相反，NFκB诱导型表达不足以提供有效的负反馈。然后，我们利用NFκB信号通路的计算模拟来确定对适当的负反馈控制至关重要的IκBα分子特性，并在生化和单细胞实时成像研究中测试所得预测结果。我们确定IκBα和IκBα-NFκB复合物的核输入和核输出，以及游离IκBα的半衰期，是诱导后NFκB抑制和随后重新激活潜力的关键决定因素。我们的工作强调，负反馈是一种涌现的系统特性，除了所需的“激活剂诱导抑制剂”关系外，还由多种分子和生物物理特性决定。
