TY - JOUR
T1 - Critical roles of IκBα and RelA phosphorylation in transitional oscillation in NF-κB signaling module
AU - Hatanaka, Naoya
AU - Seki, Takao
AU - Inoue, Jun ichiro
AU - Tero, Atsushi
AU - Suzuki, Takashi
N1 - Funding Information:
This work was supported in part by JSPS Grant-in-Aid for Scientific Research on Innovative Areas (16H06575 to JI, 16H06576 to TS,) from the Ministry of Education, Culture, Sports, Science, and Technology, Japan; the Japan Initiative for Global Research Network on Infectious Diseases (J-GRID) from the Ministry of Education, Culture, Sport, Science & Technology in Japan and the Japan Agency for Medical Research and Development (AMED)(to JI); and JSPS Core-to-Core Program, A. Advanced Research Networks (to TS)
Publisher Copyright:
© 2018 The Authors
PY - 2019/2/7
Y1 - 2019/2/7
N2 - The transcription factor NF-κB performs various cell functions, such as regulating proliferation and differentiation and blocking apoptosis, by inducing the expression of multiple genes. The shuttling of NF-κB between the cytoplasm and nucleus is involved in its transcriptional activity in the canonical NF-κB pathway. The transcription of the NF-κB target genes is regulated by the phosphorylation of both IκBα and the RelA subunit of NF-κB, suggesting that these phosphorylation events are crucial for the oscillation. In this study, we constructed a new mathematical model of NF-κB activation to explore the modulation of the oscillation by the phosphorylation of IκBα and RelA. Based on a stability analysis around the equilibrium point, we confirmed that IκBα phosphorylation added a structure with a stable periodic solution to the phosphorylation model. The stable periodic solution appeared to transiently respond to the attenuation of the concentration of active IKKβ. Because the NF-κB oscillation is caused by the periodic solution, the amplitude and period of the NF-κB oscillation in the phosphorylation model was constant regardless of the initial conditions; we defined this property as the reproducibility of the oscillation. On the other hand, the amplitude and period of the NF-κB oscillation depended on a parameter related to the RelA phosphorylation, suggesting that the oscillation period is regulated by RelA phosphorylation. In addition, the region of the periodic solution that is dependent on active IKKβ also depends on a parameter related to RelA phosphorylation. Therefore, we conclude that the phosphorylation of both IκBα and RelA regulates the robustness of the NF-κB signaling module oscillation. That is, by appropriately controlling the phosphorylation process, it becomes possible to control the NF-κB oscillation and appropriately induce the NFkB-dependent expression gene. We anticipate that this study will contribute to the future elucidation of the mechanism underlying the nuclear cytoplasmic (N-C) oscillation of NF-κB.
AB - The transcription factor NF-κB performs various cell functions, such as regulating proliferation and differentiation and blocking apoptosis, by inducing the expression of multiple genes. The shuttling of NF-κB between the cytoplasm and nucleus is involved in its transcriptional activity in the canonical NF-κB pathway. The transcription of the NF-κB target genes is regulated by the phosphorylation of both IκBα and the RelA subunit of NF-κB, suggesting that these phosphorylation events are crucial for the oscillation. In this study, we constructed a new mathematical model of NF-κB activation to explore the modulation of the oscillation by the phosphorylation of IκBα and RelA. Based on a stability analysis around the equilibrium point, we confirmed that IκBα phosphorylation added a structure with a stable periodic solution to the phosphorylation model. The stable periodic solution appeared to transiently respond to the attenuation of the concentration of active IKKβ. Because the NF-κB oscillation is caused by the periodic solution, the amplitude and period of the NF-κB oscillation in the phosphorylation model was constant regardless of the initial conditions; we defined this property as the reproducibility of the oscillation. On the other hand, the amplitude and period of the NF-κB oscillation depended on a parameter related to the RelA phosphorylation, suggesting that the oscillation period is regulated by RelA phosphorylation. In addition, the region of the periodic solution that is dependent on active IKKβ also depends on a parameter related to RelA phosphorylation. Therefore, we conclude that the phosphorylation of both IκBα and RelA regulates the robustness of the NF-κB signaling module oscillation. That is, by appropriately controlling the phosphorylation process, it becomes possible to control the NF-κB oscillation and appropriately induce the NFkB-dependent expression gene. We anticipate that this study will contribute to the future elucidation of the mechanism underlying the nuclear cytoplasmic (N-C) oscillation of NF-κB.
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U2 - 10.1016/j.jtbi.2018.11.023
DO - 10.1016/j.jtbi.2018.11.023
M3 - Article
C2 - 30496749
AN - SCOPUS:85057630808
SN - 0022-5193
VL - 462
SP - 479
EP - 489
JO - Journal of Theoretical Biology
JF - Journal of Theoretical Biology
ER -