The impact of endoplasmic reticulum morphology on IRE1 protein clustering

The endoplasmic reticulum (ER) is a cell-spanning organelle composed of a single connected network of sheets and tubes. Excess unfolded proteins in the ER, which can lead to protein aggregation and disrupt cell activities, activate IRE1 membrane signaling proteins, which form dimers, oligomers, and clusters with signaling activity that modifies gene expression via the unfolded protein response (UPR). Experiments observe IRE1 clusters with complex shapes, including wrapping around ER tubes, and dynamics consistent with coarsening behaviour. We quantitatively modeled IRE1 protein cluster dynamics on a tube surface as a lattice gas using a kinetic Monte Carlo algorithm. We show that ER tube diameter controls whether clusters can transition from approximately round to a conformation that wraps around the tube and grows without energy-penalizing interface length increases. Narrower tubes enable cluster wrapping of smaller clusters. We find that wrapped clusters on narrow tubes grow more rapidly, evaporate more slowly, and are stable at lower concentrations than equal-sized round clusters on wider tubes. Our results suggest that cluster wrapping, facilitated by narrower tubes, could be important for the growth and stability of IRE1 clusters, impacting the persistence of the UPR.