Positioning of negative feedback loops within immune signaling pathways influences gene expression noise

Signaling pathways depend on negative and positive feedback loops (NFLs and PFLs) to regulate internal noise. Across diverse organisms, signaling is regulated by NFLs that function at different cellular locations. These range from NFLs functioning upstream near signal-receiving receptors to those downstream within the nucleus. While previous studies have examined the relationship between NFLs, internal noise in signaling pathways, and network topology, none have directly addressed how the cellular location of NFLs impacts noise regulation. This is significant given the almost ubiquitous presence of multi-level regulation systems within signaling pathways. Here, we use stochastic models inspired by Imd and Toll signaling to address this gap within the context of immune signaling. We use both mechanistic and evolutionary models to demonstrate how noise is regulated by NFLs and how this, in turn, affects the host's ability to fight off infection while minimizing immunopathologic effects of excessive immune gene expression. We found that downstream NFLs reduce noise in antimicrobial peptides (AMP) expression for some parameter values. On the other hand, upstream NFLs amplify the noise, but the presence of a strong PFL can reduce this noise. Our evolutionary simulations suggest that the mechanisms through which the downstream NFL operates within the cell can affect the evolution of the upstream NFLs. The results of our study provide insight into why distinct signaling pathways are regulated by varying numbers of NFLs, which operate in different cellular locations and employ diverse mechanisms to control gene expression.