Unscrambling exit site patterns on the endoplasmic reticulum as a quenched demixing process

Speckner, Konstantin; Stadler, Lorenz-M.; Weiß, Matthias

doi:10.1016/j.bpj.2021.04.023

Cited by 5 publications

(6 citation statements)

References 53 publications

(102 reference statements)

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“…Asymmetric cell division of PVDmother may therefore provide sufficient cytoplasmic volume and ER membrane to nucleate the number of GFP::SEC-16 LLPS droplets required to establish PVD’s high ERES number. Quantitative computational models that describe ERES as self-organizing LLPS-like clusters 35,36,38 predict that smaller cells will have reduced numbers of ERESs, consistent with our observations of fewer PVD ERESs in mutants such as ceTOR/let-363 that have smaller somas. Additional studies will be required to confirm or disprove the role of LLPS in the establishment and maintenance of ERES number in neurons in vivo 41 .…”

Section: Discussionsupporting

confidence: 86%

“…An emerging body of evidence indicates that liquid-liquid phase separation (LLPS) may play an important role in ERES formation and maintenance. Previous work suggests that ERESs are dynamic, selforganizing structures [35][36][37][38] . In addition, mammalian SEC-16 exhibits liquid-liquid phase separation (LLPS) behavior in vitro and in vivo, forming condensates that recruit COPII components and other early secretory pathway proteins 39 .…”

Section: Discussionmentioning

confidence: 99%

“…It is possible that a reduction in protein translation and the resultant reduction of secretory flux subsequently reduces ERES number(Farhan et al, 2008b). In addition, a lack of TOR-mediated lipid synthesis, or a disinhibition of ER-phagy (Hamasaki et al, 2005; Zhao et al, 2015) may restrict the size of the soma and ER membrane, constraining the distance between ERES, and thus increase probability of ERES fusion to reduce ERES number(Farhan et al, 2008a; Speckner et al, 2021; Tillmann et al, 2015). Another possibility is that lack of TOR activity disinhibits autophagy of ERES directly, which may help to reduce secretion during starvation.…”

Section: Discussionmentioning

confidence: 99%

“…For instance, the dependence of initial ERES number on PVD cell size is consistent with the inherent size scaling behavior of LLPS condensates (Brangwynne, 2013). The tools developed here enable additional studies to further assess the emerging role of LLPS in the establishment and maintenance of ERESs in multicellular organisms (Alberti et al, 2019; Bevis et al, 2002; Farhan et al, 2008a; Gallo et al, 2020; Heinzer et al, 2008; Peotter et al, 2019; Speckner et al, 2021; Tillmann et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

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Neurons alter endoplasmic reticulum exit sites to accommodate dendritic arbor size

Land

Fetter

Liang

et al. 2022

Preprint

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Nervous systems exhibit dramatic diversity in cell morphology and size. How neurons regulate their biosynthetic and secretory machinery to support different cell sizes is not well understood. Endoplasmic reticulum exit sites (ERESs) are essential for maintaining secretory flux, and are required for normal dendrite development.1However, it is unknown how neurons of different size regulate the number of secretory structures to accommodate morphogenesis. InC. elegans, we find that ERES number is strongly correlated with the size of a neuron's dendritic arbor. The elaborately branched sensory neuron, PVD, has especially high ERES numbers in its soma. PVD establishes its high ERES number rapidly after birth, actively maintains ERES number as PVD grows and matures. The initial high number of ERES in PVD is driven by asymmetric cell division producing a large cell size at birth. Subsequent maintenance of ERES number requires the cell fate transcription factor MEC-3 andC. elegansTOR (ceTOR/let-363). ThisceTOR/let-363pathway integrates nutrient availability to coordinate ERES number with soma size and dendritic expansion. Our results are consistent with a model in which transcription factors, master metabolic regulators and nutrient availability coordinate to specify developmental parameters including soma size, ERES number and dendrite size, which together determine neuronal cell fate.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Neurons alter endoplasmic reticulum exit sites to accommodate dendritic arbor size

Land

Fetter

Liang

et al. 2022

Preprint

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“…Specifically, we explore the distribution of ER exit sites (ERES), which serve as the export hubs for newly synthesized proteins in the ER (39,40). The mechanism underlying the distribution of exit sites on the network is not well understood, although prior work has suggested they may arise from a process of confined diffusive aggregation (65). The process of ERES formation is not modeled explicitly here.…”

Section: E Dmentioning

confidence: 99%

ER network heterogeneity guides diffusive transport and kinetics

Scott¹,

Koning²,

Cohen³

et al. 2023

Preprint

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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. SIGNIFICANCE The endoplasmic reticulum (ER) is the largest organelle in the eukaryotic cell, forming a web of interconnected hollow tubules and sheets. The ER is central to the transport of many cellular components such as lipids, ions, and proteins. However, the impact of the ER's complex network architecture on these transport processes remains opaque. Using live-cell experiments and simulations, we demonstrate that structural heterogeneity leads to non-uniform transport of proteins to nearby regions of the ER. As a consequence, certain regions of the network function as 'hot spots' where diffusive reactants are more likely to find each other. In live cells, sites of protein export are preferentially localized to these regions.

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Endoplasmic reticulum network heterogeneity guides diffusive transport and kinetics

Scott¹,

Koning²,

Cohen³

et al. 2023

Biophysical Journal

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Unscrambling exit site patterns on the endoplasmic reticulum as a quenched demixing process

Cited by 5 publications

References 53 publications

Neurons alter endoplasmic reticulum exit sites to accommodate dendritic arbor size

Neurons alter endoplasmic reticulum exit sites to accommodate dendritic arbor size

ER network heterogeneity guides diffusive transport and kinetics

Endoplasmic reticulum network heterogeneity guides diffusive transport and kinetics

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