Computational Modelling of NF-kappa B Activation by IL-1RI and Its Co-Receptor TILRR, Predicts a Role for Cytoskeletal Sequestration of I kappa B alpha in Inflammatory Signalling

Authored by Mike Holcombe, David M Rhodes, Sarah A Smith, Eva E Qwarnstrom

Date Published: 2015

DOI: 10.1371/journal.pone.0129888

Sponsors: Biotechnology and Biological Sciences Research Council (BBSRC)

Platforms: FLAME

Model Documentation: Other Narrative Flow charts

Model Code URLs: Model code not found

Abstract

The transcription factor NF-kappa B (nuclear factor kappa B) is activated by Toll-like receptors and controlled by mechanotransduction and changes in the cytoskeleton. In this study we combine 3-D predictive protein modelling and in vitro experiments with in silico simulations to determine the role of the cytoskeleton in regulation of NF-kappa B. Simulations used a comprehensive agent-based model of the NF-kappa B pathway, which includes the type 1 IL-1 receptor (IL-1R1) complex and signalling intermediates, as well as cytoskeletal components. Agent based modelling relies on in silico reproductions of systems through the interactions of its components, and provides a reliable tool in investigations of biological processes, which require spatial considerations and involve complex formation and translocation of regulatory components. We show that our model faithfully reproduces the multiple steps comprising the NF-kappa B pathway, and provides a framework from which we can explore novel aspects of the system. The analysis, using 3-D predictive protein modelling and in vitro assays, demonstrated that the NF-kappa B inhibitor, I kappa B alpha is sequestered to the actin/spectrin complex within the cytoskeleton of the resting cell, and released during IL-1 stimulation, through a process controlled by the IL-1RI co-receptor TILRR (Toll-like and IL-1 receptor regulator). In silico simulations using the agent-based model predict that the cytoskeletal pool of I kappa B alpha is released to adjust signal amplification in relation to input levels. The results suggest that the process provides a mechanism for signal calibration and enables efficient, activation-sensitive regulation of NF-kappa B and inflammatory responses.

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