Sending proteins to dense core secretory granules: still a lot to sort out

Abstract

The intracellular sorting of peptide hormone precursors to the dense core secretory granules (DCSGs) is essential for their bioactivation. Despite the fundamental importance of this cellular process, the nature of the sorting signals for entry of proteins into DCSGs remains a source of vigorous debate. This review highlights recent discoveries that are consistent with a model in which several protein domains, acting in a cell-specific fashion and at different steps in the sorting process, act in concert to regulate the entry of proteins into DCSGs.

Effects of Muclin (Dmbt1) deficiency on the gastrointestinal system

“…Mature Muclin remains in the zymogen granule and in association with the aggregate of regulated secretory proteins. In this way, Muclin acts as a sorting receptor and helps collect regulated proteins to the TGN/nascent zymogen granule membrane and keep them there as the granule matures (14). This process is less efficient in the absence of Muclin, and delivery of proteins to the stimulus-releasable pool is slowed.…”

Proteoglycans support proper granule formation in pancreatic acinar cells

“…However, the molecular mechanisms of ZG formation and sorting of zymogens are still incompletely understood (Borgonovo et al 2006, Dikeakos & Reudelhuber 2007, Gómez-Lázaro et al 2010, Schmidt et al 2001, Schrader 2004). This also applies to the regulation and maintenance of the size and the shape of the relatively large ZG (up to 1 µm in diameter).…”

Direct binding of parotid secretory protein to phosphatidylinositol phosphates.

“…It involves selective entry of the protein into the correct immature vesicle and retention of the protein as the vesicle matures [9,17]. The vesicles containing the proteins from the trans-Golgi network (TGN) traffick them to their correct final destinations [18].…”

“…Sorting receptors have been identified in pancreas and other tissues, but no sorting receptor is known in the parotid gland. There are a variety of receptors present on the vesicles which help in sorting of specific cargo proteins, for example, carboxypeptidase present on the vesicle membrane helps in sorting of ACTH in pituitary cells [9]. Secretogranin III has been shown to be a sorting receptor for chromogranin in pituitary and pancreatic B cells [23].…”

“…These cargo proteins are transported by vesicles termed 'secretory granules' which are formed at the trans-Golgi network (TGN) of the Golgi apparatus [9]. Secretory proteins are predominantly stored at high concentrations in the dense core secretory granules of both exocrine and endocrine glands [10].…”