EIPR1 controls dense-core vesicle cargo retention and EARP complex localization in insulin-secreting cells

Topalidou, Irini; Cattin‐Ortolá, Jérôme; Hummer, Blake H.; Asensio, Cédric S.; Ailion, Michael

doi:10.1091/mbc.e18-07-0469

Cited by 16 publications

(14 citation statements)

References 52 publications

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“…Future studies could leverage correlative fluorescence microscopy and SXT ( 1 ) of the same cell by labeling live cells with ER and Golgi markers, which will enhance our ability to distinguish these features for segmentation and allow automated machine-learning segmentation approaches ( 28 ). These approaches will be useful as many questions remain on the process of vesicle maturation ( 11 , 29 ).…”

Section: Discussionmentioning

confidence: 99%

Visualizing subcellular rearrangements in intact β cells using soft x-ray tomography

et al. 2020

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Characterizing relationships between cell structures and functions requires mesoscale mapping of intact cells showing subcellular rearrangements following stimulation; however, current approaches are limited in this regard. Here, we report a unique application of soft x-ray tomography to generate three-dimensional reconstructions of whole pancreatic β cells at different time points following glucose-stimulated insulin secretion. Reconstructions following stimulation showed distinct insulin vesicle distribution patterns reflective of altered vesicle pool sizes as they travel through the secretory pathway. Our results show that glucose stimulation caused rapid changes in biochemical composition and/or density of insulin packing, increased mitochondrial volume, and closer proximity of insulin vesicles to mitochondria. Costimulation with exendin-4 (a glucagon-like peptide-1 receptor agonist) prolonged these effects and increased insulin packaging efficiency and vesicle maturation. This study provides unique perspectives on the coordinated structural reorganization and interactions of organelles that dictate cell responses.

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Section: Discussionmentioning

confidence: 99%

Visualizing subcellular rearrangements in intact β cells using soft x-ray tomography

et al. 2020

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“…Indeed, several cytosolic factors that have recently been implicated in SG biogenesis are typically associated with endocytic and retrograde pathways ( 37 – 44 ). The EARP complex and its interacting partner EIPR-1, for example, contribute to SG cargo sorting ( 45 , 46 ). It is thus tempting to speculate that retrograde pathways might contribute to SG maturation and that VPS41 could influence this process.…”

Section: Discussionmentioning

confidence: 99%

“…The copyright holder for this preprint (which this version posted April 26, 2020. ; https://doi.org/10.1101/2020.04.25.043729 doi: bioRxiv preprint (Topalidou et al, 2020;Topalidou et al, 2016). It is thus tempting to speculate that retrograde pathways might contribute to SG maturation and that VPS41 could influence this process.…”

Section: Discussionmentioning

confidence: 99%

Pancreatic β-Cell–Specific Deletion of VPS41 Causes Diabetes Due to Defects in Insulin Secretion

et al. 2020

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Insulin secretory granules (SGs) mediate the regulated secretion of insulin, which is essential for glucose homeostasis. The basic machinery responsible for this regulated exocytosis consists of specific proteins present both at the plasma membrane and on insulin SGs. The protein composition of insulin SGs thus dictates their release properties, yet the mechanisms controlling insulin SG formation, which determine this molecular composition, remain poorly understood. VPS41, a component of the endolysosomal tethering homotypic fusion and vacuole protein sorting (HOPS) complex, was recently identified as a cytosolic factor involved in the formation of neuroendocrine and neuronal granules. We now find that VPS41 is required for insulin SG biogenesis and regulated insulin secretion. Loss of VPS41 in pancreatic β-cells leads to a reduction in insulin SG number, changes in their transmembrane protein composition, and defects in granule-regulated exocytosis. Exploring a human point mutation, identified in patients with neurological but no endocrine defects, we show that the effect on SG formation is independent of HOPS complex formation. Finally, we report that mice with a deletion of VPS41 specifically in β-cells develop diabetes due to severe depletion of insulin SG content and a defect in insulin secretion. In sum, our data demonstrate that VPS41 contributes to glucose homeostasis and metabolism.

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“…Indeed, several cytosolic factors that have recently been implicated in SG biogenesis are typically associated with endocytic and retrograde pathways (Asensio et al, 2010;Cao et al, 2013;Holst et al, 2013;Paquin et al, 2016;Pinheiro et al, 2014;Sasidharan et al, 2012;Sirkis et al, 2013;Zhang et al, 2017). The EARP complex and its interacting partner EIPR-1 for example, contribute to SG cargo sorting (Topalidou et al, 2020;Topalidou et al, 2016). It is thus tempting to speculate that retrograde pathways might contribute to SG maturation and that VPS41 could influence this process.…”

Section: Discussionmentioning

confidence: 99%

Pancreatic beta-cell specific deletion of VPS41 causes diabetes due to defects in insulin secretion

Burns

Yau

Rodriguez

et al. 2020

Preprint

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Insulin secretory granules (SGs) mediate the regulated secretion of insulin, which is essential for glucose homeostasis. The basic machinery responsible for this regulated exocytosis consists of specific proteins present both at the plasma membrane and on insulin SGs. The protein composition of insulin SGs thus dictates their release properties, yet the mechanisms controlling insulin SG formation, which determines this molecular composition, remain poorly understood.VPS41, a component of the endo-lysosomal tethering HOPS complex, was recently identified as a cytosolic factor involved in the formation of neuroendocrine and neuronal granules. We now find that VPS41 is required for insulin SG biogenesis and regulated insulin secretion. Loss of VPS41 in pancreatic b-cells leads to a reduction in insulin SG number, changes in their transmembrane protein composition, and defects in granule regulated exocytosis. Exploring a human point mutation, identified in patients with neurological but no endocrine defects, we show that the effect on SG formation is independent of HOPS complex formation. Finally, we report that mice with a deletion of VPS41 specifically in β-cells develop diabetes due to severe depletion of insulin SG content and a defect in insulin secretion. In sum, our data demonstrate that VPS41 contributes to glucose homeostasis and metabolism. * *

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EIPR1 controls dense-core vesicle cargo retention and EARP complex localization in insulin-secreting cells

Cited by 16 publications

References 52 publications

Visualizing subcellular rearrangements in intact β cells using soft x-ray tomography

Visualizing subcellular rearrangements in intact β cells using soft x-ray tomography

Pancreatic β-Cell–Specific Deletion of VPS41 Causes Diabetes Due to Defects in Insulin Secretion

Pancreatic beta-cell specific deletion of VPS41 causes diabetes due to defects in insulin secretion

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