The impact of endoplasmic reticulum morphology on IRE1 protein clustering.

Abstract

The Unfolded Protein Response (UPR) is a signaling network that responds to an increased load of unfolded proteins within the Endoplasmic Reticulum (ER), referred to as ER stress. ER stress activates the transmembrane signaling protein IRE1, which subsequently forms oligomers and clusters with signaling activity that modifies target gene expression to reestablish ER homeostasis. Experiments have shown that IRE1 clusters can have complex shapes that form along the ER tube structure, including wrapping around an ER tube, and suggest that IRE1 protein clusters tend to be found on narrower ER tubes. However, the influence of ER morphology on the dynamics of these IRE1 clusters remains largely unexplored. We quantitatively modeled the dynamics of IRE1 protein clusters on a tubular surface, using a kinetic Monte Carlo algorithm that treats the IRE1 proteins as particles undergoing stochastic diffusion. We show that cluster shape exhibits a phase transition from approximately round clusters to clusters that wrap around the ER tube as a cluster becomes sufficiently large or on sufficiently narrow tubes. These wrapped clusters, which easily form on narrow tubes, evaporate much slower compared to circular clusters of equal size that form on larger tubes. The threshold concentration between cluster growth and decay is also lower for wrapped clusters compared to circular clusters, exhibiting greater stability of wrapped clusters under varying cellular concentrations of IRE1. This modeled behavior aligns with experimental observations and suggests cluster wrapping around the ER tube is important to understanding IRE1 cluster dynamics and corresponding signaling. UPR malfunction is implicated in the development of many diseases including neurodegeneration and cancer. By furthering understanding of IRE1 protein clustering, we gain insight into how ER morphology controls the IRE1 behavior and impacts UPR signaling