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Liquid-liquid phase separation facilitates the biogenesis of secretory storage granules

Anup Parchure, Meng Tian, Cierra K Boyer, Shelby C Bearrows, Kristen E Rohli, Jianchao Zhang, Bulat R Ramazanov, View ORCID ProfileYanzhuang Wang, View ORCID ProfileSamuel B Stephens, Julia von Blume
doi: https://doi.org/10.1101/2021.12.22.472607
Anup Parchure
1Department of Cell Biology, Yale University School of Medicine, New Haven, CT, USA
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Meng Tian
1Department of Cell Biology, Yale University School of Medicine, New Haven, CT, USA
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Cierra K Boyer
2Fraternal Order of Eagles Diabetes Research Center, Departments of Pharmacology and Neuroscience and Internal Medicine
3Division of Endocrinology and Metabolism, University of Iowa, Iowa City, IA, USA
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Shelby C Bearrows
2Fraternal Order of Eagles Diabetes Research Center, Departments of Pharmacology and Neuroscience and Internal Medicine
3Division of Endocrinology and Metabolism, University of Iowa, Iowa City, IA, USA
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Kristen E Rohli
2Fraternal Order of Eagles Diabetes Research Center, Departments of Pharmacology and Neuroscience and Internal Medicine
3Division of Endocrinology and Metabolism, University of Iowa, Iowa City, IA, USA
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Jianchao Zhang
4Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI, USA
5Department of Neurology, University of Michigan School of Medicine, Ann Arbor, MI, USA
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Bulat R Ramazanov
1Department of Cell Biology, Yale University School of Medicine, New Haven, CT, USA
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Yanzhuang Wang
4Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI, USA
5Department of Neurology, University of Michigan School of Medicine, Ann Arbor, MI, USA
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  • ORCID record for Yanzhuang Wang
Samuel B Stephens
2Fraternal Order of Eagles Diabetes Research Center, Departments of Pharmacology and Neuroscience and Internal Medicine
3Division of Endocrinology and Metabolism, University of Iowa, Iowa City, IA, USA
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  • ORCID record for Samuel B Stephens
Julia von Blume
1Department of Cell Biology, Yale University School of Medicine, New Haven, CT, USA
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  • For correspondence: julia.vonblume@yale.edu
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Abstract

Insulin is a key regulator of human metabolism, and its dysfunction leads to diseases such as type 2 diabetes. It remains unknown how proinsulin is targeted from the trans-Golgi network (TGN) to secretory storage granules as no cargo receptor has been identified. Chromogranin proteins (CGs) are central regulators of granule biosynthesis, and it was proposed that their aggregation is critical for this process. However, the molecular mechanism by which these molecules facilitate sorting at the TGN is poorly understood. Here, we show that CGs undergo liquid–liquid phase separation (LLPS) at low pH independently of divalent cations, such as calcium. Liquid CG condensates, but not aggregates, recruit and sort proinsulin and other granule-destined cargo molecules towards secretory granules. Cargo selectivity is independent of sequence or structural elements but is based on the size and concentration of the client molecules at the TGN. Finally, electrostatic interactions and the N-terminal intrinsically disordered domain of chromogranin B facilitate LLPS and are critical for granule formation. We propose that phase-separated CGs act as a “cargo sponge” within the TGN lumen, gathering soluble client proteins into the condensate independently of specific sequence or structural elements, facilitating receptor-independent sorting. These findings challenge the canonical TGN sorting models and provide insights into granule biosynthesis in insulin-secreting β-cells.

One sentence summary Liquid Chromogranin condensates recruit cargo molecules at the TGN for their delivery to secretory storage granules.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted December 23, 2021.
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Liquid-liquid phase separation facilitates the biogenesis of secretory storage granules
Anup Parchure, Meng Tian, Cierra K Boyer, Shelby C Bearrows, Kristen E Rohli, Jianchao Zhang, Bulat R Ramazanov, Yanzhuang Wang, Samuel B Stephens, Julia von Blume
bioRxiv 2021.12.22.472607; doi: https://doi.org/10.1101/2021.12.22.472607
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Liquid-liquid phase separation facilitates the biogenesis of secretory storage granules
Anup Parchure, Meng Tian, Cierra K Boyer, Shelby C Bearrows, Kristen E Rohli, Jianchao Zhang, Bulat R Ramazanov, Yanzhuang Wang, Samuel B Stephens, Julia von Blume
bioRxiv 2021.12.22.472607; doi: https://doi.org/10.1101/2021.12.22.472607

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