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

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.

The Regulation Network of Glycerolipid Metabolism as Coregulators of Immunotherapy-Related Myocarditis

“…Via a gene set enrichment analysis (GSEA) and the ComPPI database, we found that diacylglycerol kinase zeta (Dgkz) was significantly enriched and widely acted on various organelles. Moreover, its level in mitochondria might be closely related to VHL, PRKCA, POLR2M, SRC, and TP53 [ 43 , 44 ]. The protein encoded by the DGKZ gene belongs to the eukaryotic diacylglycerol kinase family.…”

“…The protein encoded by the DGKZ gene belongs to the eukaryotic diacylglycerol kinase family. It catalyzes the conversion of diacylglycerol (DAG) to phosphatidic acid (PA) by participating in intracellular signal cascades and signal transduction [ 43 ]. DAG and PA are lipid molecules with unique biological functions.…”

“…DAG and PA are lipid molecules with unique biological functions. They usually act as metabolic intermediates, fundamental components of biological membranes, or second messengers [ 43 , 44 ]. It is reported that DGKZ involved in the phosphatidylinositol signal pathway is closely related to pathway mechanisms in coronary artery diseases [ 45 ].…”

DGKα, Bridging Membrane Shape Changes with Specific Molecular Species of DAG/PA: Implications in Cancer and Immunosurveillance

“…The study of the molecular mechanisms governing the function of DGKα and DGKζ in T cell biology is a field of increased interest. However, in this review, the primary focus is on DGKα and the reader is referred to excellent reviews addressing the topic [ 66 , 73 , 74 ]. Nevertheless, it will be of interest to evaluate the modulation of DGKζ enzymatic activity and/or DAG substrate acyl chain specificity by membrane shape and how this compares to DGKα.…”

F-Actin Dynamics in the Regulation of Endosomal Recycling and Immune Synapse Assembly

“…In addition, proteomic analysis of the SNX27 interactome in activated T cells confirmed that SNX27-mediated trafficking involves the retromer and WASH complexes and also revealed additional cargoes that associate with SNX27 in polarized recycling to IS ( Tello-Lafoz et al, 2017 ). Among these are the lipid second messenger diacylglycerol (DAG) ( Rincón et al, 2007 ); the protein zonula occludens-2 (ZO-2), a tight junction scaffold protein recently identified in T lymphocytes; the centromere protein J (CENPJ), which acts as a microtubule plus-end tracking protein; and the Rho guanine nucleotide exchange factor 7 (ARHGEF7) ( González-Mancha and Mérida, 2020 ). These results indicate that other receptors or membrane-associated signaling components that participate in IS assembly may exploit the retromer-regulated pathway for EEs sorting and redirection to the synaptic membrane.…”