Structural controllability to unveil hidden regulation mechanisms in Unfolded Protein Response: The role of network models

The Unfolded Protein Response is the cell mechanism for maintaining the balance of properly folded proteins in the endoplasmic reticulum, the specialized cellular compartment. Although it is largely studied from a biological point of view, much of the literature lacks a quantitative analysis of such a central signaling pathway. In this work, we aim to fill this gap by applying structural controllability analysis of complex networks to several Unfolded Protein Response networks to identify crucial nodes in the signaling flow. In particular, we first build different network models of the Unfolded Protein Response mechanism, relying on data contained in various protein–protein interaction databases. Then, we identify the driver nodes, essential for overall network control, i.e., the key proteins on which external stimulation may be optimally delivered to control network behavior. Our structural controllability analysis results show that the driver nodes commonly identified across databases match with known endoplasmic reticulum stress sensors. This potentially confirms that the theoretically identified drivers correspond to the biological key proteins associated with fundamental cellular activities and diseases. In conclusion, we prove that structural controllability is a reliable quantitative tool to investigate biological signaling pathways, and it can be potentially applied to networks more complex and less explored than Unfolded Protein Response.