Cell fate in antiviral response arises in the crosstalk of IRF, NF-κB and JAK/STAT pathways

被引：0
作者：
Maciej Czerkies
Zbigniew Korwek
Wiktor Prus
Marek Kochańczyk
Joanna Jaruszewicz-Błońska
Karolina Tudelska
Sławomir Błoński
Marek Kimmel
Allan R. Brasier
Tomasz Lipniacki
机构：
[1] Polish Academy of Sciences,Institute of Fundamental Technological Research
[2] Rice University,Departments of Statistics and Bioengineering, and Program in Systems, Synthetic, and Physical Biology
[3] Silesian University of Technology,Systems Engineering Group
[4] University of Texas Medical Branch,Institute for Translational Sciences
来源：
Nature Communications | / 9卷
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摘要：
The innate immune system processes pathogen-induced signals into cell fate decisions. How information is turned to decision remains unknown. By combining stochastic mathematical modelling and experimentation, we demonstrate that feedback interactions between the IRF3, NF-κB and STAT pathways lead to switch-like responses to a viral analogue, poly(I:C), in contrast to pulse-like responses to bacterial LPS. Poly(I:C) activates both IRF3 and NF-κB, a requirement for induction of IFNβ expression. Autocrine IFNβ initiates a JAK/STAT-mediated positive-feedback stabilising nuclear IRF3 and NF-κB in first responder cells. Paracrine IFNβ, in turn, sensitises second responder cells through a JAK/STAT-mediated positive feedforward pathway that upregulates the positive-feedback components: RIG-I, PKR and OAS1A. In these sensitised cells, the ‘live-or-die’ decision phase following poly(I:C) exposure is shorter—they rapidly produce antiviral responses and commit to apoptosis. The interlinked positive feedback and feedforward signalling is key for coordinating cell fate decisions in cellular populations restricting pathogen spread.
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