Lipid-dependent coupling of secretory cargo sorting and trafficking at the trans-Golgi network

Abstract

In eukaryotic cells, the trans-Golgi network (TGN) serves as a platform for secretory cargo sorting and trafficking. In recent years, it has become evident that a complex network of lipid-lipid and lipid-protein interactions contributes to these key functions. This review addresses the role of lipids at the TGN with a particular emphasis on sphingolipids and diacylglycerol. We further highlight how these lipids couple secretory cargo sorting and trafficking for spatiotemporal coordination of protein transport to the plasma membrane.

Keywords: diacylglycerol; secretory cargo sorting; sphingolipids; trafficking; trans-Golgi network.

Fig. 1.

Vesicular biogenesis and transport at the TGN. (A) Graphical overview of the vesicular and tubular network of the TGN including cargo sorting and export domains and examples of final destinations of cargoes (basolateral membrane, endolysosomal system, apical membrane, secretory storage granules, ER). (B) Simplified depiction of the lipid content and topological distribution of lipids in the membrane.

Fig. 2.

Examples for protein–lipid and lipid–lipid interactions required for the formation of a vesicle at the TGN. (A) Clathrin-coated vesicles: AP1 is recruited by PI4P and Arf1-GTP on the TGN surface to initiate vesicle budding. (B) Noncoated vesicles: Sterol and SL domains constitute sorting domains for vesicular formation. (C) PKD integrates a cysteine-rich zinc finger domain to interact with DAG. Arf1-GTP recognizes a second C1 domain in PKD.

Fig. 3.

Regulation of lipid transfer at ER/TGN contact sites through positive and negative feedbacks. (A) Oxysterol-binding protein interacts via its PH domain with PI4P and Arf1-GTP and through its FFAT motif with ER-resident VAP receptors. As such, OSBP bridges the ER and TGN membranes and facilitates the recruitment of CERT by PI4P and VAP. CERT delivers ceramide to the TGN. (B) Overview of lipid-dependent coupling of cargo sorting with vesicle biogenesis and fission and its regulation through positive and negative feedbacks at ER-TGN contact sites.