Role of Adaptor Proteins in Secretory Granule Biogenesis and Maturation

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.

Molecular Consequences of Proprotein Convertase 1/3 (PC1/3) Inhibition in Macrophages for Application to Cancer Immunotherapy: A Proteomic Study

“…These proteins are required for transport from the endoplasmic reticulum to the Golgi stack (38) and catalyze the fusion of transport vesicles within the Golgi cisternae. By contrast, endosome-specific proteins (early, late, recycling) APPL1, VAC14, EHD4, VPS4B, ANXA6, and RAP2B and GGA2 proteins involved in protein trafficking between the trans-Golgi network (TGN) and endosomes were over-expressed in K D cells (Table IV).…”

Proteoglycans support proper granule formation in pancreatic acinar cells

“…Secretory granule biogenesis is a complex process involving the pH-dependent selective aggregation of regulated secretory proteins within the acidic environment of the TGN (for review see: Tooze et al 2001;Dikeakos & Reudelhuber 2007;Bonnemaison et al 2013) and the interaction of the aggregated zymogens with specific membrane domains. These sorting steps allow the separation of regulated secretory proteins from constitutively released cargo and their packaging in a concentrated form within secretory granules.…”

Role of Signal-Regulated Changes in Microtubule Stability Dynamics through <i>α</i>-Tubulin Phosphorylation on Ser/Tyr in Modulation of Salivary Gland Matrix Metalloproteinase-9 (MMP-9) Secretion in Response to <i>Porphyromonas gingivalis</i> and Ghrelin

“…The oral mucosal responses to P. gingivalis and its key endotoxin, cell-wall lipopolysaccharide (LPS), are characterized by the disturbances in nitric oxide synthase and cyclooxygenase systems, up-regulation in EGFR and MAPK activation, and induction in the secretion of highly glycosylated endopeptidase, metalloproteinase-9 (MMP-9) [4] [5] [6] [7] [8]. Similarly, to other regulated secretory proteins, the processing of MMP-9 along the endoplasmic reticulum (ER), Golgi, and trans-Golgi network (TGN) remains under a strict control of factors that affect the membrane recruitment and activation of various coat and cargo proteins, including ADPribosylation factors (Arfs) and protein kinase D (PKD), [9] [10] [11] [12].…”

“…The Arfs are active when bound to GTP and inactive when bound to GDP, and the activation status is controlled by the guanine nucleotide exchange factors (GEFs) [9] [13]. While GDP-bound inactive Arfs are cytosolic, the stimulus activated GTP-bound class I Arfs (Arf1, Arf2, and Arf3) rapidly translocate to the Golgi membrane compartments and assume the principal role in the recruitment of various cytosolic coat and cargo adaptor proteins, exchange factors, and lipid modifying enzymes that are essential for regulation of ER-to-Golgi traffic [11] [12]. Of particular significance to the MMP-9-containing secretory cargo processing is the role of Arf1 in the recruitment from the cytoplasm to the TGN of PKD2 [14] [15].…”