Membrane traffic in the secretory pathway

SNARE (SNAP receptor) proteins drive intracellular membrane fusion and contribute specificity to membrane trafficking. The formation of SNAREpins between membranes is spatially and temporally controlled by a network of sequentially acting accessory components. These regulators add an additional layer of specificity, arrest SNAREpin intermediates, lower the energy required for fusion, and couple membrane fusion to triggering signals. The functional activity of some of these regulators determines the plasticity of regulated exocytosis. (Part of a Multi-author Review)     

Membrane traffic in the secretory pathway

Vesicular transport is the basic communication mechanism between different compartments in a cell and with the environment. In this review I discuss the principles of vesicle generation and consumption with particular emphasis on the different types of coat proteins and the timing of the shedding of the coat proteins from transport containers. In recent years it has become clear that there are more coat complexes than the classical COPI, COPII and clathrin coats. These additional coats may generate vesicles that transport cargo in a temporally and/or spatially controlled manner. Work over the last years suggests that GTP hydrolysis occurs early during vesicle biogenesis, destabilizing the coat perhaps before fission of the vesicle from the donor membrane occurs. Recent findings imply, however, that tethers at the receiving compartment specifically detect the coat on vesicle. (Part of a Multi-author Review)     

Membrane traffic in the secretory pathway

Vesicular transport is the basic communication mechanism between different compartments in a cell and with the environment. In this review I discuss the principles of vesicle generation and consumption with particular emphasis on the different types of coat proteins and the timing of the shedding of the coat proteins from transport containers. In recent years it has become clear that there are more coat complexes than the classical COPI, COPII and clathrin coats. These additional coats may generate vesicles that transport cargo in a temporally and/or spatially controlled manner. Work over the last years suggests that GTP hydrolysis occurs early during vesicle biogenesis, destabilizing the coat perhaps before fission of the vesicle from the donor membrane occurs. Recent findings imply, however, that tethers at the receiving compartment specifically detect the coat on vesicle. (Part of a Multi-author Review)     

Membrane traffic in the secretory pathway

Secretion is a fundamental biological activity of all eukaryotic cells by which they release certain substances in the extracellular space. It is considered a specialized mode of membrane trafficking that is achieved by docking and fusion of secretory vesicles to the plasma membrane (i.e., exocytosis). Secretory vesicle traffic is thought to be regulated by a family of Rab small GTPases, which are regulators of membrane traffic that are common to all eukaryotic cells. Classically, mammalian Rab3 subfamily members were thought to be critical regulators of secretory vesicle exocytosis in neurons and endocrine cells, but recent genetic and proteomic studies indicate that Rab3 is not the sole Rab isoform that regulates secretory vesicle traffic. Rather, additional Rab isoforms, especially Rab27 subfamily members, are required for this process. In this article I review the current literature on the function of Rab isoforms and their effectors in regulated secretory vesicle traffic.     

Membrane traffic in the secretory pathway

Membrane trafficking is crucial in the homeostasis of the highly compartmentalized eukaryotic cells. This compartmentalization occurs both at the organelle level, with distinct organelles maintaining their identities while also intensely interchanging components, and at a sub-organelle level, with adjacent subdomains of the same organelle containing different sets of lipids and proteins.Acentral question in the field is thus how this compartmentalization is established and maintained despite the intense exchange of components and even physical continuities within the same organelle. The phosphorylated derivatives of phosphatidylinositol, known as the phosphoinositides, have emerged as key components in this context, both as regulators of membrane trafficking and as finely tuned spatial and temporal landmarks for organelle and sub-organelle domains. The central role of the phosphoinositides in cell homeostasis is highlighted by the severe consequences of the derangement of their metabolism caused by genetic deficiencies of the enzymes involved, and from the systematic hijacking of phosphoinositide metabolism that pathogens operate to promote their entry and/or survival in host cells. (Part of a Multi-author Review)     

Membrane traffic in the secretory pathway

The steady-state localisation of membrane proteins in the endocytic system is the result of many sorting events that occur at various points throughout the endosomal pathway. A protein that has been endocytosed from the plasma membrane or sorted at the trans-Golgi network (TGN) and transported to an endosome will ultimately be delivered to one of three destinations: the plasma membrane, the TGN or the lysosome. Where a membrane protein is trafficked to depends on the interactions between sorting motifs present in the membrane protein and the machinery that can decode these motifs. Much of the protein machinery that recognises sorting motifs is conserved from yeast toman, and in this review I will discuss this machinery and the motifs that govern endosomal protein sorting. (Part of a Multi-author Review)     

Membrane traffic in the secretory pathway

Cholesterol, certain lipids, membrane-bound and soluble proteins, as well as viruses that are synthesized in the endoplasmic reticulum (ER), reach the plasma membrane (PM) via non-classical pathway(s) that remain poorly understood. Typical for this transport is (i) its insensitivity to brefeldin A (BFA), which dissociates selected coat complexes from membranes, resulting in the disassembly of the Golgi apparatus; (ii) its rapid kinetics as compared to the classical secretory pathway; and (iii) its role in the trafficking of lipid raft components. Based on results showing that the intermediate compartment (IC) at the ER-Golgi boundary constitutes a stable tubular network that maintains its dynamics in the presence of BFA, we propose that two bidirectional Golgi-bypass pathways to the PM exist, a direct route from early IC elements, and another, reminiscent of the yeast secretory pathway, from late IC elements via the endosomal system. These pathways have implications for the organization of the secretory processes in different cell types.     

Molecular aspects of membrane fission in the secretory pathway

Membrane fission is essential in various intracellular dissociative transport steps. The molecular mechanisms by which endocytic vesicles detach from the plasma membrane are being rapidly elucidated. Much less is known about the fission mechanisms operating at Golgi tubular networks; these include the Golgi transport and sorting stations, the trans-Golgi and cis-Golgi networks, where the geometry and physical properties of the membranes differ from those at the cell surface. Here we discuss the lipid and protein machineries that have so far been related to the fission process, with emphasis on those acting in the Golgi complex. Received 10 May 2002; received after revision 20 June 2002; accepted 26 June 2002 RID="*" ID="*"Corresponding author.     

The role of serpins in the surveillance of the secretory pathway

Serpins (serine protease inhibitors) constitute a class of proteins with an unusually wide spectrum of different functions at extracellular sites and within the nucleocytoplasmic compartment that extends from protease inhibition to hormone transport and regulation of chromatin organization. Recent investigations reveal a growing number of serpins acting in secretory pathway organelles, indicating that they are not simply cargo destined for export, but fulfill distinct roles within the classical organelle-coupled trafficking system. These findings imply that some serpins are part of a quality control system that monitors the export and possibly import routes of eukaryotic cells. The molecular targets of these serpins are often unknown, opening new avenues for future research.     

Inhibitors of protein translocation across membranes of the secretory pathway: novel antimicrobial and anticancer agents

Proteins routed to the secretory pathway start their journey by being transported across biological membranes, such as the endoplasmic reticulum. The essential nature of this protein translocation process has led to the evolution of several factors that specifically target the translocon and block translocation. In this review, various translocation pathways are discussed together with known inhibitors of translocation. Properties of signal peptide-specific systems are highlighted for the development of new therapeutic and antimicrobial applications, as compounds can target signal peptides from either host cells or pathogens and thereby selectively prevent translocation of those specific proteins. Broad inhibition of translocation is also an interesting target for the development of new anticancer drugs because cancer cells heavily depend on efficient protein translocation into the endoplasmic reticulum to support their fast growth.     

A di-arginine ER retention signal regulates trafficking of HCN1 channels from the early secretory pathway to the plasma membrane

Hyperpolarization-activated cyclic nucleotide-gated 1 (HCN1) channels carry I_h, which contributes to neuronal excitability and signal transmission in the nervous system. Controlling the trafficking of HCN1 is an important aspect of its regulation, yet the details of this process are poorly understood. Here, we investigated how the C-terminus of HCN1 regulates trafficking by testing for its ability to redirect the localization of a non-targeted reporter in transgenic Xenopus laevis photoreceptors. We found that HCN1 contains an ER localization signal and through a series of deletion constructs, identified the responsible di-arginine ER retention signal. This signal is located in the intrinsically disordered region of the C-terminus of HCN1. To test the function of the ER retention signal in intact channels, we expressed wild type and mutant HCN1 in HEK293 cells and found this signal negatively regulates surface expression of HCN1. In summary, we report a new mode of regulating HCN1 trafficking: through the use of a di-arginine ER retention signal that monitors processing of the channel in the early secretory pathway.     

Uncharted secretory nerves in the parotid gland of the dog

Zusammenfassung Es wird in Versuchen an Hunden gezeigt, dass man nach Durchschneidung und Degeneration des Nervus auriculotemporalis reflektorisch eine beachtliche Parotissekretion auslösen kann. Histochemisch konnten zudem viele acetylcholinesterasepositive Nerven nachgewiesen werden.

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Supported by grant No. K67-14X-539-03 from the Swedish Medical Research Council.     

Storing of secretory material inside the perinuclear space

Zusammenfassung In Zellen des Subcommissuralorgans unbehandelter Wistar-Ratten und in neurosekretorischen Zellen NaCl-belasteter Teichmolche wurden voluminöse Erweiterungen der Perinuclearzisterne beobachtet, die beim Teichmolch zur Ausbildung grosser Vakuolen führen können. Perinuclearzisterne und Vakuolen enthalten ein feingranuläres, mässig elektronendichtes Material (proteinreiches Sekret). Es wird eine intranucleäre Synthese von Oligopeptiden oder Proteinen für möglich gehalten.     

A possible role of microtubules in the C cells secretory mechanism

Riassunto Le modalità di secrezione dei granuli contenenti Calcitonina da parte delle cellule C sono state studiate in tiroidi di cane in condizioni normali e in coltura organotipica con alto tenore di calcio. È stata notata la presenza di numerosi microtubuli alla periferia delle cellule e alcune immagini suggeriscono un attacco dei microtubuli ai granuli secretori. Viene prospettato che i microtubuli abbiano importanza nel meccanismo di secrezione delle cellule C e forse delle cellule della serie APUD in generale, e che questo possa essere del tipo «emiocitosi».     

Membrane fusion

The factors involved in the regulation of biological membrane fusion and models proposed for the molecular mechanism of biomembrane fusion are reviewed. The results obtained in model systems are critically discussed in the light of the known properties of biomembranes and characteristics of biomembrane fusion. Biological membrane fusion is a local-point event; extremely fast, non-leaky, and under strict control. Fusion follows on a local and most probably protein-modulated destabilization, and a transition of the interacting membranes from a bilayer to a non-bilayer lipid structure. The potential role of type II non-bilayer preferring lipids and of proteins in the local destabilization of the membranes is evaluated. Proteins are not only responsible for the mutual recognition of the fusion partners, but are most likely also to be involved in the initiation of biomembrane fusion, by locally producing or activating fusogens, or by acting as fusogens.     

Lipids in the silk-glands ofBombyx mori and their probable role in secretory metabolism

Résumé Dans les glandes séricigènes des mues de la chenille duBombyx mori, les lipides sudanophiles s'accumulent progressivement jusqu'à la 5e mue et s'épuisent complètement pendant la formation du cocon. Une étude systématique des divers systèmes d'enzymes montre que les lipides fournissent par oxydation-réduction l'énergie nécessaire au métabolisme sécrétoire des cellules des glandes pendant les dernières mues.