Key Points
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The trans-Golgi network (TGN) is an assembly of pleiomorphic tubular membranes that emanates from the trans-Golgi pole. It has multiple crucial roles in intracellular transport as a sorting node for secretory cargo, a biosynthetic centre for sphingolipids and the interface between the exocytic and endocytic pathways.
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The TGN is an extremely dynamic structure, and its extent (size and number of tubules) largely depends on the amount of cargo and membrane flowing through it. We therefore propose that this organelle is an assembly of cargo-sorting domains under extrusion as tubules for export out of the Golgi complex.
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The main destinations of TGN-derived carriers are the apical and basolateral plasma membrane, the early and late endosomes, the secretory granules and other specialized compartments in specialized cells. Each of these destinations corresponds to at least one carrier type, although different carriers might ferry specific cargo proteins to the same acceptor organelle.
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The final destination of each specific cargo type is determined by the sorting signals in the cargo molecule. These signals are decoded by a complex cytosolic machinery, within which coat proteins and adaptors have a major role.
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The formation of these pleiomorphic tubular TGN carriers can be divided into three main stages: cargo sorting into a forming tubule; extrusion of the tubular carrier along microtubules by molecular motors; and fission of the elongated tubule into a free carrier. Each of these stages involves a multi-component machinery, only parts of which have been identified to date.
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Future research in the TGN area will require the unravelling of the further components and their assigning to the appropriate carrier formation stage within specific Golgi export pathways. Another key challenge will be to determine the regulatory mechanisms by which the functions of the TGN are controlled and coordinated both at the organelle level within the secretory pathway, and between the TGN and other global cellular functions and responses.
Abstract
The composition and identity of cell organelles are dictated by the flux of lipids and proteins that they receive and lose through cytosolic exchange and membrane trafficking. The trans-Golgi network (TGN) is a major sorting centre for cell lipids and proteins at the crossroads of the endocytic and exocytic pathways; it has a complex dynamic structure composed of a network of tubular membranes that generate pleiomorphic carriers targeted to different destinations. Live-cell imaging combined with three-dimensional tomography has recently provided the temporal and topographical framework that allows the assembly of the numerous molecular machineries so far implicated in sorting and trafficking at the TGN.
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Acknowledgements
We are extremely grateful to R. Polishchuk for providing the images shown in Fig. 2, we thank the members of the Department of Cell Biology and Oncology (DCBO) for useful discussions, C. P. Berrie for editorial assistance and E. Fontana for artwork. The authors acknowledge the support of Telethon and Italian Association for Cancer Research (AIRC). We would also like to apologize to those whose primary research could not be cited owing to space constraints.
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Glossary
- Early/sorting endosomes
-
Tubular, vesicular structures that receive direct input from the plasma membrane and that are precursors of the mature endosomes; they have a key role in sorting material for recycling or degradation.
- Late endosomes
-
Endosomes that receive cargo from early/sorting endosomes and deliver them to lysosomes, where the cargo molecules are degraded. They contain many vesicles in their lumen, and are also known as multivesicular bodies.
- Recycling endosomes
-
Endosomal compartments that are mainly composed of narrow-diameter tubules. A large fraction of recycling membrane components pass through the recycling endosomes, which might also be an intermediate station in trans-Golgi network to plasma membrane trafficking.
- Golgi stack
-
A stack of ordered, flat, membranous cisternae with a recognizable cis–trans polarity.
- Secretory granules
-
Organelles present in secretory cells (exocrine and endocrine cells) that derive from the trans-Golgi network. They function as a reservoir for enzymes and hormones, and they release their contents in response to extracellular stimuli.
- SNAREs
-
(Soluble N-ethyl-maleimide-sensitive fusion protein (NSF)-attachment-protein (SNAP) receptors). A family of membrane-tethered, coiled-coil proteins that regulate fusion reactions and targeted specificity in the vacuolar system.
- Sorting signals
-
Sequence motifs or structural determinants that interact with specific recognition proteins and determine the trafficking or localization of cellular proteins.
- Correlative light-electron microscopy
-
(CLEM). A technique by which the ultrastructure and dynamics of an individual object can be observed.
- Clathrin
-
The main component of a vesicle coating that is involved in membrane transport in both the endocytic and biosynthetic pathways.
- Membrane contact sites
-
Sites of close apposition of membranes (≤10 nm), either belonging to the same organelle (that is, between ER elements or Golgi cisternae) or to different organelles (usually between the ER and another organelle, such as mitochondria, the plasma membrane, vacuoles or the Golgi complex).
- Coatomer protein complex-II
-
(COPII). A protein complex consisting of two heterodimers, SEC23–SEC24 and SEC13–SEC31, that are recruited to ER exit sites by the small GTPase SAR1. COPII promotes the formation of Golgi-directed carriers.
- Coatomer protein complex-I
-
(COPI). A protein complex that is recruited to membranes by ARF (ADP-ribosylation factor) GTPases and that mediates intra-Golgi and Golgi-to-ER retrograde transport.
- Transcytosis
-
A process by which materials are transported across a polarized cell from one membrane domain (for example, the basolateral plasma membrane) to another (for example, the apical plasma membrane).
- VSVG
-
(Vesicular stomatitis virus glycoprotein). A viral glycoprotein that in its temperature-sensitive form (ts045) is used as a synchronizable secretory reporter protein, which exploits its property of being retained in the ER at 40 °C, and is transported along the exocytic pathway upon removal of the 40 °C temperature block.
- Adaptors
-
Proteins that recruit clathrin to membranes and concentrate specific transmembrane proteins in clathrin-coated areas of the membrane.
- GGA protein
-
(Golgi-localized, γ-ear-containing, ADP ribosylation factor (ARF)-binding protein). A monomeric clathrin adaptor that mediates trans-Golgi network-to-endosome transport of mannose-6-phosphate receptors and other transmembrane proteins. They are also involved in targeting transmembrane proteins to the multivesicular-body pathway.
- Membrane microdomain
-
A localized membrane region that differs from surrounding regions in their lipid composition and order. There are probably many types of lipid microdomains that coexist within the same membrane bilayer. Lipid rafts are one type of membrane microdomain.
- GPI anchor
-
The function of this post-translational modification is to attach proteins to the exoplasmic leaflet of membranes and possibly to specific domains therein. The anchor is made of one molecule of phosphatidylinositol, to which a carbohydrate chain is linked through the C6 hydroxyl of the inositol, and it is linked to the protein through an ethanolamine phosphate moiety.
- GRIP-golgins
-
A family of coiled-coil proteins that includes golgin-245, golgin-97, CCG88 and CCG185, all of which have a C-terminal, 50-amino-acid domain that is known as the GRIP domain, which is responsible for their targeting to the trans-Golgi network.
- Transendosomal route
-
A route that connects the trans-Golgi network and the plasma membrane, and passes through recycling endosomes.
- BAR family
-
A family of proteins that contains the BAR (Bin, amphiphysin and Rvs) domain, a banana-shaped domain that binds to highly curved membranes.
- Lipid flippase
-
A protein that facilitates the translocation of a phospholipid or glycosphingolipid from one leaflet of a membrane bilayer to the other.
- Mannose-6-phosphate receptor
-
(M6PR). Receptor that is located at the TGN and, at low levels, at the plasma membrane. It is responsible for targeting several soluble lysosomal hydrolases from the Golgi complex, through endosomes, to the lysosomes.
- Actin comets
-
Short actin filaments that function to propel intracellular organelles or pathogens.
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De Matteis, M., Luini, A. Exiting the Golgi complex. Nat Rev Mol Cell Biol 9, 273–284 (2008). https://doi.org/10.1038/nrm2378
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DOI: https://doi.org/10.1038/nrm2378
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