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

Anup Parchure; Meng Tian; Danièle Stalder; Cierra K Boyer; Shelby C Bearrows; Kristen E Rohli; Jianchao Zhang; Felix Rivera-Molina; Bulat R Ramazanov; Sushil K Mahata; Yanzhuang Wang; Samuel B Stephens; David C Gershlick; Julia von Blume

doi:10.1083/jcb.202206132

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

Journal article

Open access

Peer reviewed

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

Anup Parchure, Meng Tian, Danièle Stalder, Cierra K Boyer, Shelby C Bearrows, Kristen E Rohli, Jianchao Zhang, Felix Rivera-Molina, Bulat R Ramazanov, Sushil K Mahata, …

The Journal of cell biology, Vol.221(12), p.1

12/05/2022

DOI: 10.1083/jcb.202206132

PMCID: PMC9526250

PMID: 36173346

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Abstract

Insulin is synthesized by pancreatic β-cells and stored into secretory granules (SGs). SGs fuse with the plasma membrane in response to a stimulus and deliver insulin to the bloodstream. The mechanism of how proinsulin and its processing enzymes are sorted and targeted from the trans-Golgi network (TGN) to SGs remains mysterious. No cargo receptor for proinsulin has been identified. Here, we show that chromogranin (CG) proteins undergo liquid-liquid phase separation (LLPS) at a mildly acidic pH in the lumen of the TGN, and recruit clients like proinsulin to the condensates. Client selectivity is sequence-independent but based on the concentration of the client molecules in the TGN. We propose that the TGN provides the milieu for converting CGs into a "cargo sponge" leading to partitioning of client molecules, thus facilitating receptor-independent client sorting. These findings provide a new receptor-independent sorting model in β-cells and many other cell types and therefore represent an innovation in the field of membrane trafficking.

Chromogranins - metabolism

Cytoplasmic Granules - metabolism

Golgi Apparatus - metabolism

Humans

Insulin - metabolism

Insulin-Secreting Cells - metabolism

Proinsulin - metabolism

Secretory Vesicles - metabolism

Details

Title: Subtitle: Liquid-liquid phase separation facilitates the biogenesis of secretory storage granules
Creators: Anup Parchure - Yale University
Meng Tian - Yale University
Danièle Stalder - University of Cambridge
Cierra K Boyer - University of Iowa
Shelby C Bearrows - University of Iowa
Kristen E Rohli - University of Iowa
Jianchao Zhang - University of Michigan
Felix Rivera-Molina - Yale University
Bulat R Ramazanov - Yale University
Sushil K Mahata - University of California San Diego
Yanzhuang Wang - University of Michigan
Samuel B Stephens - University of Iowa
David C Gershlick - University of Cambridge
Julia von Blume - Yale University
Resource Type: Journal article
Publication Details: The Journal of cell biology, Vol.221(12), p.1
DOI: 10.1083/jcb.202206132
PMID: 36173346
PMCID: PMC9526250
NLM abbreviation: J Cell Biol
ISSN: 0021-9525
eISSN: 1540-8140
Grant note: T32 GM008629 / NIGMS NIH HHS Wellcome Trust R35 GM130331 / NIGMS NIH HHS 3R01GM134083-03S1 / Administrative Supplement GM134083-01 / NIH HHS
Language: English
Date published: 12/05/2022
Academic Unit: Fraternal Order of Eagles Diabetes Research Center; Endocrinology and Metabolism; Internal Medicine
Record Identifier: 9984360059302771

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