Interplay Between SNX27 and DAG Metabolism in the Control of Trafficking and Signaling at the IS.

Natalia González-Mancha,Isabel Mérida

doi:10.3390/ijms21124254

Abstract

Recognition of antigens displayed on the surface of an antigen-presenting cell (APC) by T-cell receptors (TCR) of a T lymphocyte leads to the formation of a specialized contact between both cells named the immune synapse (IS). This highly organized structure ensures cell–cell communication and sustained T-cell activation. An essential lipid regulating T-cell activation is diacylglycerol (DAG), which accumulates at the cell–cell interface and mediates recruitment and activation of proteins involved in signaling and polarization. Formation of the IS requires rearrangement of the cytoskeleton, translocation of the microtubule-organizing center (MTOC) and vesicular compartments, and reorganization of signaling and adhesion molecules within the cell–cell junction. Among the multiple players involved in this polarized intracellular trafficking, we find sorting nexin 27 (SNX27). This protein translocates to the T cell–APC interface upon TCR activation, and it is suggested to facilitate the transport of cargoes toward this structure. Furthermore, its interaction with diacylglycerol kinase ζ (DGKζ), a negative regulator of DAG, sustains the precise modulation of this lipid and, thus, facilitates IS organization and signaling. Here, we review the role of SNX27, DAG metabolism, and their interplay in the control of T-cell activation and establishment of the IS.

Highlights

The immune synapse (IS) consists on a highly organized, dynamic macromolecular structure that enables cell–cell communication between immune cells
Not too much is known about the retriever in IS formation, SNX17 is found with the T-cell receptor (TCR) at the IS, and its silencing limits TCR and lymphocyte function-associated antigen 1 (LFA-1) expression at the cell surface, affecting IS formation and T-cell activation [25]
Precise regulation of intracellular transport is crucial in polarized cells, which depend on active membrane trafficking at specific sites to carry out their functions [137,138,139]

Summary

Introduction

The immune synapse (IS) consists on a highly organized, dynamic macromolecular structure that enables cell–cell communication between immune cells. Not too much is known about the retriever in IS formation, SNX17 is found with the TCR at the IS, and its silencing limits TCR and lymphocyte function-associated antigen 1 (LFA-1) expression at the cell surface, affecting IS formation and T-cell activation [25] Contrary to their recycling, cargoes can be transported to lysosomes for their degradation, which is achieved via the activity of endosomal sorting complexes required for transport (ESCRT) [26,27]. Particular phospholipids named phosphoinositides (PI) work together with Rab GTPases, regulatory proteins that recruit effectors involved in the formation of vesicles, as well as their traffic and fusion Both types of molecules define endosomal and organelle identity [30,31,32]. We summarize the current knowledge of the roles of lipids, with a special focus on the lipid second messenger diacylglycerol (DAG), as well as that of the transport protein SNX27, in the spatio-temporal regulation of trafficking and signaling that sustains the IS

Diacylglycerol and Phosphatidic Acid in the Regulation of the Immune Synapse

SNX-FERM and SNX-BAR Subfamilies

The SNX27–Retromer Multiprotein Complex Is Involved in Protein Recycling

Concluding Remarks