Oscillation dynamics underlie functional switching of NF-κB for B-cell activation.

Kazuyuki Aihara,Alexander Hoffmann,Noriko Yumoto,Gouhei Tanaka,Kentaro Inoue,Mariko Okada-Hatakeyama,Marcelo Behar,Hisaaki Shinohara

doi:10.1038/npjsba.2016.24

Abstract

Transcription factor nuclear factor kappa B (NF-κB) shows cooperative switch-like activation followed by prolonged oscillatory nuclear translocation in response to extracellular stimuli. These dynamics are important for activation of the NF-κB transcriptional machinery, however, NF-κB activity regulated by coordinated actions of these dynamics has not been elucidated at the system level. Using a variety of B cells with artificially rewired NF-κB signaling networks, we show that oscillations and switch-like activation of NF-κB can be dissected and that, under some conditions, these two behaviors are separated upon antigen receptor activation. Comprehensive quantitative experiments and mathematical analysis showed that the functional role of switch activation in the NF-κB system is to overcome transient IKK (IκB kinase) activity to amplify nuclear translocation of NF-κB, thereby inducing the prolonged NF-κB oscillatory behavior necessary for target gene expression and B-cell activation.

Highlights

Transcription factor nuclear factor kappa B (NF-κB) is activated in response to a variety of extracellular stimuli and regulates transcription of multiple genes involved in cell fate decisions.[1]Given its central role in many cellular processes, the regulation of this transcription factor is critical in several human diseases.[2,3,4,5] In the canonical signaling pathway in B lymphocytes, NF-κB is activated by B-cell receptor (BCR) signaling via a complex chain of events involving protein kinase C β (PKCβ), CARD containing MAGUK protein[1] (CARMA1, known as CARD11), transforming growth factor (TGF) β-activated kinase 1 (TAK1, known as MAP3K7) and IκB kinase β (IKKβ)
We show that switch-like activation caused by positive feedback loops is essential to compensate for the transient nature of upstream IKK activity and to induce amplified accumulation of nuclear NF-κB, which is in turn necessary for inducing subsequent oscillations for target gene expression
We extended the models, incorporating details of the formation of the CARMA1, B cell chronic lymphocytic leukemia 10 (BCL10), and/or mucosa-associated lymphoid tissue (MALT) lymphoma translocation gene 1 (MALT1) (CBM signalosome) complex, which has critical roles in regulating BCR signaling

Summary

Introduction

Transcription factor nuclear factor kappa B (NF-κB) is activated in response to a variety of extracellular stimuli and regulates transcription of multiple genes involved in cell fate decisions.[1]. Given its central role in many cellular processes, the regulation of this transcription factor is critical in several human diseases.[2,3,4,5] In the canonical signaling pathway in B lymphocytes, NF-κB is activated by B-cell receptor (BCR) signaling via a complex chain of events involving protein kinase C β (PKCβ), CARD containing MAGUK protein[1] (CARMA1, known as CARD11), transforming growth factor (TGF) β-activated kinase 1 (TAK1, known as MAP3K7) and IκB kinase β (IKKβ). After stimulation, phosphorylationinduced degradation of the IκBs by IKKβ liberates NF-κB for nuclear translocation, where it regulates transcription of target genes (Figure 1a, Supplementary Section 1). NF-κB activity is further regulated by multiple feedback loops in the network, resulting in complex dynamical activity profiles.[6,7,8,9,10,11,12,13]

Methods

Results

Conclusion