Abstract
In the regulated secretory pathway, secretory granules (SGs) store peptide hormones that are released on demand. SGs are formed at the trans-Golgi network and must undergo a maturation process to become responsive to secretagogues. The production of mature SGs requires concentrating newly synthesized soluble content proteins in granules whose membranes contain the appropriate integral membrane proteins. The mechanisms underlying the sorting of soluble and integral membrane proteins destined for SGs from other proteins are not yet well understood. For soluble proteins, luminal pH and divalent metals can affect aggregation and interaction with surrounding membranes. The trafficking of granule membrane proteins can be controlled by both luminal and cytosolic factors. Cytosolic adaptor proteins (APs), which recognize the cytosolic domains of proteins that span the SG membrane, have been shown to play essential roles in the assembly of functional SGs. Adaptor protein 1A (AP-1A) is known to interact with specific motifs in its cargo proteins and with the clathrin heavy chain, contributing to the formation of a clathrin coat. AP-1A is present in patches on immature SG membranes, where it removes cargo and facilitates SG maturation. AP-1A recruitment to membranes can be modulated by Phosphofurin Acidic Cluster Sorting protein 1 (PACS-1), a cytosolic protein which interacts with both AP-1A and cargo that has been phosphorylated by casein kinase II. A cargo/PACS-1/AP-1A complex is necessary to drive the appropriate transport of several cargo proteins within the regulated secretory pathway. The Golgi-localized, γ-ear containing, ADP-ribosylation factor binding (GGA) family of APs serve a similar role. We review the functions of AP-1A, PACS-1, and GGAs in facilitating the retrieval of proteins from immature SGs and review examples of cargo proteins whose trafficking within the regulated secretory pathway is governed by APs.
Highlights
THE REGULATED SECRETORY PATHWAY Neuroendocrine cells synthesize, process, and store peptide hormones so that they are available for secretion upon demand [1]
DIRECTIONS Little is known about the cytosolic machinery involved in sorting membrane proteins at the trans-Golgi network (TGN) for their entry into immature secretory granules (SGs)
A recent study in Drosophila suggested that adaptor proteins (APs)-3, the AP transporting proteins to lysosomes, was involved in sorting proteins into the regulated secretory pathway at the TGN level [170]
Summary
Reviewed by: Juan Ramon Peinado, University of Castilla la Mancha, Spain J. After exiting the endoplasmic reticulum, prohormones are transported to the Golgi apparatus, where additional posttranslational modifications such as oligosaccharide maturation and phosphorylation can occur (Figure 1) [5, 7] When they reach the trans-Golgi network (TGN), prohormones, and their processing enzymes are concentrated into granules budding from the TGN; these structures presumably represent newly forming SGs [1]. These new SGs are immature and must undergo a maturation process before they are capable of secreting peptide hormone in response to secretagogue. Maturation involves remodeling of the immature SG membrane by removal of non-regulated secretory proteins and excess membrane; this process involves clathrincoated vesicles mediated by adaptor proteins (APs) (Figure 1)
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