Protein dispersion and facilitated diffusion in the endoplasmic reticulum

The endoplasmic reticulum (ER) forms a dynamic network of lipid membrane sheets and tubules from the cell nucleus to the periphery. Its many functional roles include the distribution of lipids, ions and proteins throughout the cell, but the impact of morphology on transport remains poorly understood. Pairing our novel propagator-driven approach for fast agent-based simulations of particles diffusing on tubular networks with in vivo data on the spreading of photoactivated membrane proteins, we quantify how local ER network structure determines protein spreading. Our results demonstrate that network structure and diffusion explain much, but not all, of the behavior of ER membrane proteins. Tubule growth and rearrangement are also implicated in determining protein dispersion. We describe a new model for cargo loading and sorting at ER exit sites, relying on `facilitated diffusion’ of secretory cargo to a region of weak binding surrounding a narrow exit site neck. We link local network structure to the rate of cargo accumulation, and compare these results to in vivo measurements following synchronized cargo release. Using theory and live-cell imaging, we highlight the structure-function relationship of the ER as an intracellular transport hub with a uniquely complex morphology.