Review
From endosomes to the trans-Golgi network

https://doi.org/10.1016/j.semcdb.2014.04.024Get rights and content

Highlights

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    The endosome-to-trans Golgi network (TGN) retrograde trafficking is an important pathway to divert endocytic cargoes from lysosomal degradation.

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    Common methods in studying the retrograde trafficking are evaluated.

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    Components involved, such as retromer, small GTPases, coat proteins, SNAREs and tethering factors, are reviewed.

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    The roles of the retrograde trafficking in signal transduction and diseases are discussed.

Abstract

The retrograde trafficking from endosomes to the trans-Golgi network (TGN) is one of the major endocytic pathways to divert proteins and lipids away from lysosomal degradation. Retrograde transported cargos enter the TGN via two itineraries from either the early endosome/recycling endosome or the late endosome and involve various machinery components such as retromer, sorting nexins, clathrin, small GTPases, tethering factors and SNAREs. Recently, the pathway has been recognized for its role in signal transduction, physiology and pathogenesis of human diseases.

Section snippets

The pathway to recycle the secretory machinery

In the secretory or biosynthetic pathway, cargos targeted to the endoplasmic reticulum (ER) sequentially pass through Golgi cisternae to the trans-Golgi network (TGN). The TGN is a hub of the membrane trafficking network of a mammalian cell. By default, secretory cargos are constitutively delivered to the plasma membrane (PM) for exocytosis. Alternatively, cargos with sorting signals could diverge from this default route to reach endosomes via the TGN-to-endosome pathway. The reverse pathway,

Two endocytic pathways leading to the TGN

The EE/RE-to-TGN and the LE-to-TGN pathways have been proposed as two major endocytic itineraries leading to the TGN. They were originally defined and represented by Tac-TGN38 and Tac-furin [9], [10] (Fig. 1), which are the fusion of two type I transmembrane proteins, the extracellular domain of interleukin 2 receptor α subunit (Tac) and the cytosolic domain of rat TGN38 or furin. Shortly after endocytosis, both Tac-TGN38 and Tac–furin first reach the EE. However, their subsequent itineraries

Cargos utilizing the endosome-to-TGN trafficking

Although the TGN-to-PM trafficking is rapid and generally considered to be by default, most PM membrane cargos do not take retrograde routes back to the TGN as revealed by monitoring the re-sialylation (a TGN specific enzymatic reaction) of de-sialylated surface membrane proteins [18]. This finding indicates that the endosome-to-TGN pathways could be restricted to privileged cargos. On the other hand, almost all yeast membrane proteins residing on the late Golgi (equivalent to the TGN in

Methodology

Two types of methods have been used to assay the endosome-to-TGN trafficking in mammalian cells. The biochemical type of assays take advantage of unique enzymatic reactions of the TGN, such as sialylation of glycans and tyrosine sulfation, catalyzed by TGN localized enzymes – sialyltransferase [43] and tyrosyl protein sulfotransferase [22], [44], [45], respectively. In tyrosine sulfation based assay, an artificial tyrosine sulfation site is engineered within the luminal region of cargos, such

Molecular mechanism

Many endosomal or Golgi proteins have been implicated in the endosome-to-TGN trafficking. However, the detailed cellular studies of many of them are still lacking. Therefore, it is still hard to combine all proteins as a picture within the frame of our knowledge. This review attempts to integrate those that we know the best.

In the endosome-to-TGN trafficking, membrane carriers, such as vesicles or tubules, emerge from endosomes, travel along cytoskeleton tracks, tether at and then fuse with the

Retrograde trafficking in cellular signaling and neurodegenerative diseases

Recent advancement in this field revealed important roles of retrograde trafficking in cellular signaling and neurodegenerative diseases through its core machinery–retromer. The Wnt family secreted morphogens are essential for the proper patterning of various tissues in metazoans [109]. The secretion of Wnt depends on its interaction with Wntless, a multi-transmembrane protein cycling among the PM, the endosome and the Golgi [110]. After biosynthesis of Wnt in the ER, Wnt enters the secretory

Conclusions and future directions

The endosome-to-TGN retrograde trafficking has been recognized as an important route to retrieve cargos from the endo-lysosome degradation pathway. Core machinery components involved in this trafficking pathway have been identified. Especially, the sorting, packing and/or targeting of many cargos converge on the retromer protein complex on the endosomal membrane. However, we do not have a coherent and complete molecular picture on how they work together in vivo, which requires extensive future

Acknowledgements

This work was supported by the following grants to L.L.: NMRC/CBRG/007/2012 and AcRF Tier1 RG 18/11.

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