Chemical Reaction Network Theory elucidates sources of multistability in interferon signaling

Bistability has important implications in signaling pathways, since it indicates a potential cell decision between alternative outcomes. We present two approaches developed in the framework of the Chemical Reaction Network Theory for easy and efficient search of multiple steady state behavior in signaling networks (both with and without mass conservation), and apply them to search for sources of bistability at different levels of the interferon signaling pathway. Different type I interferon subtypes and/or doses are known to elicit differential bioactivities (ranging from antiviral, antiproliferative to immunomodulatory activities). How different signaling outcomes can be generated through the same receptor and activating the same JAK/STAT pathway is still an open question. Here, we detect bistability at the level of early STAT signaling, showing how two different cell outcomes are achieved under or above a threshold in ligand dose or ligand-receptor affinity. This finding could contribute to explain the differential signaling (antiviral vs apoptotic) depending on interferon dose and subtype (α vs β) observed in type I interferons.Author summary: Type 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.