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Review
. 2020 Jun 15;21(12):4254.
doi: 10.3390/ijms21124254.

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

Natalia González-Mancha  1 , Isabel Mérida  1
Affiliations
Review

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

Natalia González-Mancha et al. Int J Mol Sci. .

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.

Keywords: SNX27; diacylglycerol; diacylglycerol kinase; immune synapse; intracellular trafficking; retromer.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Diacylglycerol (DAG) metabolism contributes to immune synapse (IS) structure and associated signaling. (A) Upon T-cell activation, PLC--γ1-mediated phosphatidylinositol (4,5)-bisphosphate (PtdIns(4,5)P2) hydrolysis leads to the generation of inositol triphosphate (IP3) and DAG, which in turn can be converted to phosphatidic acid (PA) via the activity of a diacylglycerol kinase (DGK). (B) Schematic representation of proteins recruited and modulated by DAG and PA at the synapsis of T lymphocytes, indicating the cellular processes in which they are involved. MVB, multivesicular bodies; nPKC, novel protein kinase C (PKC); cPKC, conventional PKC; aPKC, atypical PKC.
Figure 2
Figure 2
Sorting nexin 27 (SNX27)–retromer architecture and function in intracellular trafficking. (A) SNX27 establishes N-terminal postsynaptic density 95/discs large/zonula occludens-1 (PDZ) domain-mediated interactions with cargo and the Vps26 retromer subunit, as well as 4.1/ezrin/radixin/moesin (FERM) domain-dependent engagement with the retromer SNX-BAR (Bin, amphiphysin, Rvs) and the Wiskott–Aldrich syndrome protein and SCAR homolog (WASH) complex. Moreover, both the SNX-BAR dimer and the WASH complex directly bind to the cargo selection subcomplex of the retromer. (B) SNX27–retromer promotes endosomal trafficking of cargo to the plasma membrane; this multiprotein complex is associated to the cytosolic face of the endosomal membrane mainly through binding of the SNX27 phox homology (PX) domain and SNX-BARs to phosphoinositides (PI). Endosomal localization is further stabilized by SNX27 cargo recognition and cargo-selection subcomplex (CSC) interaction with SNX-BAR and SNX27. Actin polymerization mediated by the WASH complex and membrane remodeling induced by SNX-BAR mediate tubule formation and scission of the cargo-enriched endosome subdomain. A frontal view of the endosomal tubule coated by the SNX27–retromer is shown. Images modified from References [17,112]. (C) The generated cargo-loaded vesicles are subsequently recycled to the cell surface, preventing their lysosomal degradation. Image modified from Reference [111].
Figure 3
Figure 3
SNX27 is recruited to the IS and facilitates trafficking of cargoes toward this structure. In resting T cells, SNX27 is mainly found at PtdIns(3)P-positive endosomes. Upon T-cell activation, these endosomes polarize toward the cell–cell interface, and a fraction of this protein accumulates at the IS. This event is facilitated by the SNX27 PDZ domain and the interaction of its FERM domain with PtdIns(4,5)P2- and/or PtdIns(3,4,5)P3-enriched membrane regions. Binding of SNX27 to its cargoes can drive their mobility to the IS, as observed for zonula occludens-2 (ZO-2).
Figure 4
Figure 4
SNX27 participates in the regulation of DAG metabolism at the IS through interaction with DGKζ. (A) DGKζ and SNX27 proteins interact in a PDZ-dependent manner. The high-affinity DGKζ C-terminal sequence EDQETAV with possible phosphorylation sites (red) and positively charged amino acids (blue) is indicated. (B) Engagement of antigen–TCR triggers PLC-γ1 activation, resulting in DAG production and its accumulation at the IS. Likewise, SNX27 and the DAG-negative regulator DGKζ translocate to the IS simultaneously with PtdIns(3,4,5)P3 and DAG generation. SNX27 sustains the stability and localization of this kinase, facilitating the regulation of DAG and its downstream signaling pathways.
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References

    1. Batista F.D., Iber D., Neuberger M.S. B cells acquire antigen from target cells after synapse formation. Nature. 2001;411:489–494. doi: 10.1038/35078099. - DOI - PubMed
    1. Davis D.M., Chiu I., Fassett M., Cohen G.B., Mandelboim O., Strominger J.L. The human natural killer cell immune synapse. Proc. Natl. Acad. Sci. USA. 1999;96:15062–15067. doi: 10.1073/pnas.96.26.15062. - DOI - PMC - PubMed
    1. Stinchcombe J.C., Bossi G., Booth S., Griffiths G.M. The Immunological Synapse of CTL Contains a Secretory Domain and Membrane Bridges. Immunity. 2001;15:751–761. doi: 10.1016/S1074-7613(01)00234-5. - DOI - PubMed
    1. Alcover A., Thoulouze M.-I. Vesicle Traffic to the Immunological Synapse: A Multifunctional Process Targeted by Lymphotropic Viruses. In: Saito T., Batista F.D., editors. Immunological Synapse. Vol. 340. Springer Berlin Heidelberg; Berlin/Heidelberg, Germany: 2010. pp. 191–207. Current Topics in Microbiology and Immunology. - PubMed
    1. Martín-Cófreces N.B., Baixauli F., Sánchez-Madrid F. Immune synapse: Conductor of orchestrated organelle movement. Trends Cell Biol. 2014;24:61–72. doi: 10.1016/j.tcb.2013.09.005. - DOI - PMC - PubMed