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  • Review Article
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Retrograde transport from endosomes to the trans-Golgi network

Nature Reviews Molecular Cell Biology volume 7, pages 568–579 (2006)Cite this article

Key Points

  • Some intracellular transmembrane proteins, such as acid-hydrolase receptors, processing peptidases and SNAREs, undergo retrograde transport from endosomes to the trans-Golgi network (TGN) as part of their normal trafficking. This retrograde-transport pathway is exploited by a subset of bacterial and plant protein toxins to enable them to reach the endoplasmic reticulum and eventually the cytosol.

  • Recent studies have begun to unravel the molecular machinery that is involved in this retrograde transport. Acid-hydrolase receptors such as Saccharomyces cerevisiae vacuolar protein sorting-10 (Vps10) protein and the mammalian mannose 6-phosphate receptors (MPRs) are selected for retrograde transport by a five-subunit complex named 'retromer'. In mammalian cells, this complex is mainly associated with tubules that emanate from vacuolar, early–late endosomal intermediates.

  • Other components of the retrograde-transport machinery for the mammalian MPRs are the clathrin-associated, heterotetrameric AP1 (adaptor protein-1) complex, the clathrin-associated monomeric adaptor epsinR (epsin-related) and PACS1 (phosphofurin acidic-cluster-sorting-1), which are also associated with early endosomes and derived tubules. Furthermore, the small GTPase Rab9 and its effector TIP47 (tail-interacting protein of 47 kDa) mediate the retrograde transport of MPRs from late endosomes.

  • Although MPRs seem to be capable of being transported to the TGN from both early and late endosomal compartments, protein toxins undergo retrograde transport exclusively from early endosomes. Not surprisingly then, protein toxins and MPRs share some components of the retrograde-transport machinery that is associated with early endosomal compartments.

  • The location of molecular devices that are involved in the retrograde transport of MPRs and protein toxins highlights the existence of an extensive 'tubular endosomal network' (TEN) that both sorts and recycles cargoes to various destinations, including different domains of the plasma membrane, the limiting membrane of lysosomes and lysosome-related organelles, and specialized storage vesicles, in addition to the TGN.

  • The TEN probably gives rise to retrograde-transport carriers that dock at and fuse with the TGN by a process that relies on various small GTPases of the Arl (ADP-ribosylation factor-like) and Rab families, tethering factors and SNARE complexes.

  • This diversity of compartments and molecular devices underscores the existence of multiple pathways for retrograde transport from endosomes to the TGN.

Abstract

A subset of intracellular transmembrane proteins such as acid-hydrolase receptors, processing peptidases and SNAREs, as well as extracellular protein toxins such as Shiga toxin and ricin, undergoes 'retrograde' transport from endosomes to the trans-Golgi network. Here, we discuss recent studies that have begun to unravel the molecular machinery that is involved in this process. We also propose a central role for a 'tubular endosomal network' in sorting to recycling pathways that lead not only to the trans-Golgi network but also to different plasma-membrane domains and to specialized storage vesicles.

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Figure 1: Components of the molecular machinery that mediates retrograde transport from endosomes to the trans-Golgi network.
Figure 2: Ultrastructural localization of various sorting devices to tubular endosomes.
Figure 3: A schematic representation of the 'tubular endosomal network'.

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Acknowledgements

We thank W. Smith for help with the figure in BOX 1, D. Banfield, G. Fischer von Mollard, W. Hong, H. Pelham and K. Sandvig for helpful discussions, and G. Mardones and J. Hurley for comments on the manuscript.

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Authors and Affiliations

  1. Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Juan S. Bonifacino & Raul Rojas

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  1. Juan S. Bonifacino
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Correspondence to Juan S. Bonifacino or Raul Rojas.

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Glossary

Type-I integral membrane protein

A protein that contains a single membrane-spanning domain, with the C terminus orientated towards the cytosol and the N terminus orientated towards the lumen of a membrane compartment or in an extracellular direction.

Clathrin

A structural protein that polymerizes onto membranes as a polyhedral lattice, which often leads to the formation of clathrin-coated vesicles. The sorting of transmembrane cargoes into these vesicles is mediated by various adaptor proteins that link the cytosolic domains of the cargoes to the clathrin lattice.

Retrotranslocation

Transport from the lumen of the endoplasmic reticulum (ER) to the cytosol. This process is the reverse of protein import into the ER, and is generally followed by proteins that are targeted for ER-associated degradation (ERAD).

Divalent-metal-containing phosphoesterases

A family of enzymes that contain two divalent cations and hydrolyse phosphate–ester bonds. This family includes various phosphatases and nucleases.

COPI

(coatomer protein complex-I). A heteroheptameric protein complex that is recruited to membranes by Arf (ADP-ribosylation factor) GTPases and that mediates intra-Golgi transport and retrograde transport from the Golgi complex to the endoplasmic reticulum.

COPII

(coatomer protein complex-II). A protein complex consisting of two heterodimers, Sec23–Sec24 and Sec13–Sec31, that are recruited to endoplasmic reticulum (ER) exit sites by the small GTPase Sar1. COPII promotes the formation of vesicles that mediate the export of cargo from the ER to the Golgi complex.

Rab GTPases

Members of the Ras superfamily of small GTP-binding proteins that function in the tethering and docking of vesicles to their target compartments prior to membrane fusion. Rab proteins also participate in cargo selection, vesicle budding and organelle motility.

PX domain

(Phox-homology domain). These domains are lipid- and protein-interaction domains that consist of 100–130 amino acids and are defined by sequences that are found in two components of the phagocyte NADPH oxidase (phox) complex.

BAR domain

This domain gets its acronym from the fact that it is found in the proteins Bin, amphiphysin and Rvs. This domain dimerizes and binds to highly curved membranes such as those found in the tubular elements of endosomes.

AP3

(adaptor protein-3). A heterotetrameric protein complex that associates with endosomes and promotes the transport of tyrosinase to melanosomes and lysosome-associated membrane proteins to lysosomes.

Dynamins

Large G-proteins that belong to a protein superfamily that, in eukaryotes, includes classical dynamins, dynamin-like proteins, mitofusins and atlastins. Dynamins are involved in the scission of a wide range of vesicles and organelles.

Palmitoylation

A post-translational modification that involves the addition of a 16-carbon fatty acid, palmitic acid, to a cysteine residue through a thioester bond.

Arl GTPases

Small Arf (ADP-ribosylation factor)-like GTPases that participate in the fusion of retrograde transport carriers with the trans-Golgi network.

GGA proteins

(Golgi-localized, γ-ear-containing, ADP-ribosylation-factor-binding proteins). Monomeric clathrin adaptors that mediate the transport of mannose 6-phosphate receptors and other transmembrane proteins between the trans-Golgi network and endosomes. They also seem to have a role in targeting transmembrane proteins to the multivesicular-body pathway.

ESCRT machinery

(Endosomal sorting complex required for transport machinery). Machinery that comprises three ESCRT complexes that mediate the sorting of transmembrane cargo from the limiting membrane into the intralumenal vesicles of multivesicular bodies.

Multivesicular bodies

Endocytic organelles that contain small vesicles in their interior and that are intermediate compartments in the lysosomal degradation pathway.

EHD proteins

(Eps15-homology-domain proteins). These proteins are part of the machinery that returns internalized transmembrane proteins to the plasma membrane.

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Bonifacino, J., Rojas, R. Retrograde transport from endosomes to the trans-Golgi network. Nat Rev Mol Cell Biol 7, 568–579 (2006). https://doi.org/10.1038/nrm1985

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