ER network heterogeneity guides diffusive transport and kinetics

TL;DR

This study investigates how the heterogeneity and dynamics of the endoplasmic reticulum network influence diffusive protein transport, revealing that network structure creates hotspots that facilitate molecular interactions and ER exit site localization.

Contribution

The paper combines experimental imaging, computational modeling, and analytical methods to show that ER network heterogeneity significantly impacts diffusive transport and reaction sites.

Findings

ER network heterogeneity creates 'hot spots' for molecular interactions.

ER dynamics are slow enough to have minimal impact on diffusion.

ER exit sites are preferentially located in highly accessible regions.

Abstract

The endoplasmic reticulum (ER) is a dynamic network of interconnected sheets and tubules that orchestrates the distribution of lipids, ions, and proteins throughout the cell. The impact of its complex, dynamic morphology on its function as an intracellular transport hub remains poorly understood. To elucidate the functional consequences of ER network structure and dynamics, we quantify how the heterogeneity of the peripheral ER in COS7 cells affects diffusive protein transport. In vivo imaging of photoactivated ER membrane proteins demonstrates their non-uniform spreading to adjacent regions, in a manner consistent with simulations of diffusing particles on extracted network structures. Using a minimal network model to represent tubule rearrangements, we demonstrate that ER network dynamics are sufficiently slow to have little effect on diffusive protein transport. Furthermore, stochastic simulations reveal a novel consequence of ER network heterogeneity: the existence of 'hot spots' where sparse diffusive reactants are more likely to find one another. Intriguingly, ER exit sites are disproportionately found in these highly accessible regions. Combining in vivo experiments with analytic calculations, quantitative image analysis, and computational modeling, we demonstrate how structure guides diffusive protein transport and reactions in the ER.