The endoplasmic reticulum (ER), a network of membranous sheets and pipes, supports functions encompassing biogenesis of secretory proteins and delivery of functional solutes throughout the cell1,2. Molecular mobility through the ER network enables these functionalities, but diffusion alone is not sufficient to explain luminal transport across supramicrometre distances. Understanding the ER structure–function relationship is critical in light of mutations in ER morphology-regulating proteins that give rise to neurodegenerative disorders3,4. Here, super-resolution microscopy and analysis of single particle trajectories of ER luminal proteins revealed that the topological organization of the ER correlates with distinct trafficking modes of its luminal content: with a dominant diffusive component in tubular junctions and a fast flow component in tubules. Particle trajectory orientations resolved over time revealed an alternating current of the ER contents, while fast ER super-resolution identified energy-dependent tubule contraction events at specific points as a plausible mechanism for generating active ER luminal flow. The discovery of active flow in the ER has implications for timely ER content distribution throughout the cell, particularly important for cells with extensive ER-containing projections such as neurons.
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Source image-series data for Fig. 1e and Supplementary Figs. 2 and 4e,f have been provided as Supplementary Videos 1, 2 and 8–10 respectively; and statistical information for Fig. 2 and Supplementary Fig. 2 have been provided in Supplementary Table 1. Custom code has been deposited in the Zenodo database (https://doi.org/10.5281/zenodo.1317630) with experimental raw data (https://doi.org/10.5281/zenodo.1318129). All other data supporting the findings of this study are available from the corresponding authors on reasonable request.
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We are grateful to M. Gratian and M. Bowen (CIMR, Cambridge) and G. Strachan (Institute of Metabolic Science, Cambridge) for assistance in establishing microscopy data acquisition approaches; and S. Preissler (CIMR, Cambridge) for discussion. This study was supported by grants from the Wellcome Trust to D.R. (Wellcome 200848/Z/16/Z, WT: UNS18966); the Wellcome Trust Strategic Award for core facilities to the Cambridge Institute for Medical Research (Wellcome 100140); EPSRC (EP/L015889/1 and EP/H018301/1), MRC (MR/K015850/1 and MR/K02292X/1) and the Wellcome Trust (3-3249/Z/16/Z and 089703/Z/09/Z) to C.F.K.; an FRM team research grant to D.H.; and a DIM fellowship from Ile-de-France to P.P.; UK Dementia Research Institute grant to E.A. D.R. is a Wellcome Trust Principal Research Fellow. E.A. is a United Kingdom Dementia Research Institute Fellow.