Examining the Link Between Peroxiredoxin Proteins and Mutually Exclusive Transcription Factor Activation With a Mathematical Model

TL;DR

This study uses a mathematical model to explore how peroxiredoxin proteins influence transcription factor activation during oxidative stress, revealing switch-like responses and predicting effects of protein knockouts.

Contribution

It introduces a dynamical systems model linking peroxiredoxin hyperoxidation to transcriptional responses, providing testable predictions for future experiments.

Findings

Hyperoxidation of peroxiredoxins acts as an ultrasensitive switch.

Simultaneous signaling by Prx I and II is necessary for stress categorization.

Model predicts effects of Prx knockouts and peroxide affinity on stress response.

Abstract

Oxidative stress is a fundamental stimulus to which eukaryotic cells respond via many channels. Among these channels are both protein systems that process oxidative stress, such as the 2-Cys peroxiredoxin-thioredoxin system (PTRS), as well as changes in transcriptional activity that target outcomes such as growth, damage control and repair, or cell death. Recent work has revealed connections between the PTRS and temporal phases of transcriptional activity involving famous transcription factors like p53 and FOXO1. To examine potential mechanisms for these connections, we implement an existing dynamical systems mathematical model for the PTRS. We hypothesize that dose-dependent hyperoxidation events enact ultrasensitive switches by which the PTRS can categorize stress severity and activate appropriate transcriptional responses. Using numerical simulations of the PTRS in human cells, we provide a proof of principle for staggered, switchlike hyperoxidation of peroxiredoxins (Prx) as well as an underlying mechanism requiring simultaneous signaling by Prx I and II. Then, we use our model to make testable predictions about individual Prx knockouts as well as the affinity for hydrogen peroxide of Prx across oxidation states. This study provides direction for future experimental work and sheds light into the mechanisms underlying oxidative stress response in human cells.