![]() Remarkably, proinsulin and its processing enzymes do not have a conserved structural or sequence-specific motif for sorting them into ISGs, and a cargo receptor has not yet been identified ( Bauerfeind and Huttner, 1993 Thiele et al., 1997 Arvan and Halban, 2004 Chung et al., 1989).Ĭhromogranin (CG) proteins are highly expressed in pancreatic β-cells and other specialized secretory cells and play a significant role in the packaging of granule-destined proteins ( Bearrows et al., 2019 Kim et al., 2001 Tooze and Huttner, 1990). Importantly, proinsulin sorting to ISGs must be tightly coordinated with its processing by Carboxypeptidase E (CPE), Proprotein convertase 1/3 (PC1/3), and PC2 ( Hutton, 1989 Germanos et al., 2021 Arvan, 2004). ![]() The TGN sorts and targets proteins to their destination through vesicular transport carriers ( Kienzle and von Blume, 2014 Ramazanov et al., 2021). These secretory proteins travel across the Golgi stacks and are sorted at the trans-Golgi network (TGN Ford et al., 2021). Secretory proteins are synthesized, glycosylated, folded, and quality checked in the endoplasmic reticulum (ER) lumen before being loaded onto carriers for transport to the Golgi apparatus ( Brandizzi and Barlowe, 2013 Dancourt and Barlowe, 2009 Miller and Barlowe, 2010). 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. ![]() 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. ![]() Client selectivity is sequence-independent but based on the concentration of the client molecules in the TGN. 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. No cargo receptor for proinsulin has been identified. The mechanism of how proinsulin and its processing enzymes are sorted and targeted from the trans-Golgi network (TGN) to SGs remains mysterious. ![]() SGs fuse with the plasma membrane in response to a stimulus and deliver insulin to the bloodstream. Insulin is synthesized by pancreatic β-cells and stored into secretory granules (SGs). ![]()
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