Mathematical Modelling of the Function of Ubiquitylation in TNFR1-Mediated NF-κB Signalling

摘要

The tumor necrosis factor receptor 1 (TNFR1) pathway plays a crucial role in immune signalling and development by controlling cell growth and death [7]. The binding of tumor necrosis factor-α (TNFα) to TNFR1 can either trigger two different forms of cell death - apoptosis and necroptosis - or promote cell survival due to the activation of the transcription factor nuclear factor-κB (NF-κB) [5]. A dysregulation of this pathway can result in chronic diseases and cancer-related inflammation and features a strictly controlled regulatory network [6]. Therefore, the logic of the pathway regulation is of interest for cancer research to recognise the mechanisms that determine the outcome of death receptor stimulation. The TNFR1 pathway displays a complex signalling network with different regulatory features like feedforward, feedback, and crosstalk. The membrane bound receptor signalling complex (RSC) builds a crucial part in the signalling cascade, since the duration and composition of its formation determine the activity of the effector kinases and thereby the capacity of gene expression. In this context, ubiquitylation plays a pivotal role as an important post-translational modification process [2]. Just recently a novel component of the NF-κB pathway was discovered being responsible for linear ubiquitylation events, which enhance the activation of the transcription factor [6]. In order to elucidate the complex dynamics of these interwoven pathways, we established an interaction network in a systems biology approach using the Petri net formalism. Therefore, we constructed a Petri net with focus on TNFR1-mediated NF-κB pathway to examine the assembly of macromolecular complexes orchestrating the decision between survival and cell death. Here, we especially consider ubiquitylation events and their effect on signalling to NF-κB.