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Chemical Reaction Network Theory elucidates sources of multistability in interferon signaling

AutorOtero-Muras, Irene ; Yordanov, Pancho; Stelling, Joerg
Fecha de publicación2017
EditorPublic Library of Science
CitaciónPLoS Computational Biology 13(4): e1005454 (2017)
ResumenType I interferons (IFNs) regulate a variety of cell functions, exhibiting, amongst others, antiviral, antiproliferative and immunomodulatory activities. Due to their anticancer effects, type I IFNs have a long record of applications in clinical oncology. It is still an open question how type I IFNs generate so diverse signaling outcomes by activating the same receptor at the cell membrane and triggering the same JAK/STAT pathway. It has been experimentally shown that differences in ligand affinity towards the receptor, IFN dose and receptor density are translated into different activities, but the underlying mechanisms of differential responses remain elusive. Looking for potential cell decision processes that could help answering this question, we explore the capacity for bistability at different levels of the IFN pathway. The search for bistability sources in interferon signaling is performed within the framework of Chemical Reaction Network Theory, by adapting previous results to the specific context of signaling pathways. Surprisingly, we find a source of bistability already at the early STAT signaling level. As a result, we show that the pathway has the capacity to translate a difference in affinity or IFN dose into a binary decision between High/Low or Low/High activation profiles of two IFN transcription factors (ISGF3 and STAT1-STAT1 homodimers) responsible for the upregulation of two different families of interferon stimulated genes: ISRE and GAS
Descripción28 páginas, 6 figuras.-- This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Versión del editorhttps://doi.org/10.1371/journal.pcbi.1005454
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