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Bioinformatics, Computational and Systems Biology

Bioinformatics, Computational and Systems Biology - Poster Session C

Poster A7 - Inflammasomes and Kinetic Modeling of DNA Sensor Protein Polymerization

Friday, October 25, 2024

10:00 AM - 11:00 AM EST

Location: Exhibit Hall E, F & G

Presenting Author(s)

JT

Jeremiah Tobin (he/him/his)

Student
University of South Carolina, United States

Primary Investigator(s)

MU

Mark Uline

Program Director, Biomedical Engineering; Associate Professor, Chemical Engineering
University of South Carolina, United States

Co-Author(s)

CW

Clinton Webb, PhD

Professor, Biomedical Engineering Director, Cardiovascular Translational Research Center
University of South Carolina
Columbia, South Carolina, United States

Introduction: Hypertension is a leading health concern linked to chronic stress. Stress leads to the creation of reactive oxygen species in the mitochondria of endothelial cells. This causes the oxidation, segmentation, and release into the cytosol of mitochondrial DNA. This mtDNA is a nucleation point for inflammasome sensor proteins like AIM2 and NLRP3 which polymerize on the mtDNA fragments and recruit ASC which binds to procaspase-1. Procaspase-1 is cleaved to form mature caspase-1 which induces the formation of the inflammatory cytokines IL-18 and IL-1β. This leads to inflammation, pyroptosis, and hypertension. Even though inflammasomes are widely implicated as a sensing platform in immune responses they have not been the subject of heavy quantitative study and modeling. A minimalistic model of inflammasome assembly has previously been researched in Digital signaling network drives the assembly of the AIM2-ASC inflammasome. However, recent studies have shown new facets of this protein polymerization mechanism.

Materials and

Methods: Previously proposed mechanisms for inflammasome formation corresponded to the established assembly mechanism of IFI16, an immune sensor protein that polymerizes on foreign DNA within the nucleus of cells. However recent studies have shown that AIM2 does not display linear diffusion along DNA which is a central component of the IFI16 mechanism. This leads to a discrepancy among the current literature on the assembly of AIM2 monomers on DNA. In this work, we expand on kinetic models put forth by previous literature by introducing mass balance equations, accounting for length-dependent DNA binging explicitly, and proposing a mechanism for AIM2 polymerization independent linear diffusion of AIM2 monomers.
The kinetic model created from these insights yields a set of ordinary differential equations that is capable of predicting the development of AIM2 polymers within the cytosol. These equations were then fit to existing in-vitro data of AIM2 polymerization on 600 bp DNA to determine the kinetic rate constants for the association of monomers. This was then compared to in vitro data of AIM2 polymerization on other lengths of DNA to establish the model’s accuracy.

Results, Conclusions, and Discussions: The assembly of AIM2 polymers on DNA involves many molecular interactions. Herin, we show these can be characterized via kinetic rate equations forming a set of ODEs. The created model characterizes the fundamental mechanism of the system and predicts the formation of AIM2 polymers based on the initial concentrations of AIM2 and DNA. The predictive capability of this model suggests that the mechanism the model is based on is an adequate approximation of the actual molecular mechanism taking place. Future progress of this work looks to observe inflammasome formation in vivo to establish its impact and determine any intervening pathways within a complete cell.

Acknowledgements (Optional):