SNX17 Affects T Cell Activation by Regulating TCR and Integrin Recycling

A key component in T cell activation is the endosomal recycling of receptors to the cell surface, thereby allowing continual integration of signaling and Ag recognition. One protein potentially involved in TCR transport is sorting nexin 17 (SNX17). SNX proteins have been found to bind proteins involved in T cell activation, but specifically the role of SNX17 in receptor recycling and T cell activation is unknown. Using immunofluorescence, we find that SNX17 colocalizes with TCR and localizes to the immune synapse in T– conjugates. Significantly, knockdown of the SNX17 resulted in fewer T–APC conjugates, lower CD69, TCR, and LFA-1 surface expression, as well as lower overall TCR recycling compared with control T cells. Lastly, we identified the 4.1/ezrin/radixin/moesin domain of SNX17 as being responsible in the binding and trafficking of TCR and LFA-1 to the cell surface. These data suggest that SNX17 plays a role in the maintenance of normal surface levels of activating receptors and integrins to permit optimum T cell activation at the immune synapse.

[1]  R. Fässler,et al.  Sorting nexin 31 binds multiple β integrin cytoplasmic domains and regulates β1 integrin surface levels and stability. , 2014, Journal of molecular biology.

[2]  T. Boggon,et al.  Structural Determinants for Binding of Sorting Nexin 17 (SNX17) to the Cytoplasmic Adaptor Protein Krev Interaction Trapped 1 (KRIT1)* , 2014, The Journal of Biological Chemistry.

[3]  G. Pazour,et al.  Specific recycling receptors are targeted to the immune synapse by the intraflagellar transport system , 2014, Journal of Cell Science.

[4]  Ricardo Henriques,et al.  Regulated vesicle fusion generates signaling nanoterritories that control T cell activation at the immunological synapse , 2013, The Journal of experimental medicine.

[5]  Katharina Gaus,et al.  VAMP7 controls T cell activation by regulating the recruitment and phosphorylation of vesicular Lat at TCR-activation sites , 2013, Nature Immunology.

[6]  J. Tavaré,et al.  A global analysis of SNX27–retromer assembly and cargo specificity reveals a function in glucose and metal ion transport , 2013, Nature Cell Biology.

[7]  Z. Lou,et al.  Dedicator of Cytokinesis 8 Interacts with Talin and Wiskott-Aldrich Syndrome Protein To Regulate NK Cell Cytotoxicity , 2013, The Journal of Immunology.

[8]  Huadong Liu,et al.  Structural basis for endosomal trafficking of diverse transmembrane cargos by PX-FERM proteins , 2013, Proceedings of the National Academy of Sciences.

[9]  A. Mangalam,et al.  WASH Knockout T Cells Demonstrate Defective Receptor Trafficking, Proliferation, and Effector Function , 2012, Molecular and Cellular Biology.

[10]  N. Hogg,et al.  A role for Rap2 in recycling the extended conformation of LFA-1 during T cell migration , 2012, Biology Open.

[11]  R. Fässler,et al.  Sorting nexin 17 prevents lysosomal degradation of β1 integrins by binding to the β1-integrin tail , 2012, Nature Cell Biology.

[12]  P. Cullen,et al.  SNX17 protects integrins from degradation by sorting between lysosomal and recycling pathways , 2012, The Journal of cell biology.

[13]  J. Norman,et al.  The Arp2/3 activator WASH regulates α5β1-integrin-mediated invasive migration , 2011, Journal of Cell Science.

[14]  Severine I. Gharbi,et al.  Translocation dynamics of sorting nexin 27 in activated T cells , 2011, Journal of Cell Science.

[15]  M. Tsujimoto,et al.  Adaptor protein sorting nexin 17 interacts with the scavenger receptor FEEL-1/stabilin-1 and modulates its expression on the cell surface. , 2010, Biochimica et biophysica acta.

[16]  A. Alcover,et al.  Vesicle traffic to the immunological synapse: a multifunctional process targeted by lymphotropic viruses. , 2010, Current topics in microbiology and immunology.

[17]  D. Billadeau,et al.  A FAM21-containing WASH complex regulates retromer-dependent sorting. , 2009, Developmental cell.

[18]  Colin K. Choi,et al.  Integrins in cell migration – the actin connection , 2009, Journal of Cell Science.

[19]  P. Cullen.  Endosomal sorting and signalling: an emerging role for sorting nexins , 2008, Nature Reviews Molecular Cell Biology.

[20]  L. Samelson,et al.  Rab35 and Its GAP EPI64C in T Cells Regulate Receptor Recycling and Immunological Synapse Formation* , 2008, Journal of Biological Chemistry.

[21]  A. Echard.  Membrane traffic and polarization of lipid domains during cytokinesis. , 2008, Biochemical Society transactions.

[22]  Marie Malissen,et al.  The proline-rich sequence of CD3ε controls T cell antigen receptor expression on and signaling potency in preselection CD4+CD8+ thymocytes , 2008, Nature Immunology.

[23]  M. Maginnis,et al.  NPXY Motifs in the β1 Integrin Cytoplasmic Tail Are Required for Functional Reovirus Entry , 2008, Journal of Virology.

[24]  L. Coscoy,et al.  Downregulation of the T-Cell Receptor Complex and Impairment of T-Cell Activation by Human Herpesvirus 6 U24 Protein , 2007, Journal of Virology.

[25]  N. Hogg,et al.  The role of the integrin LFA‐1 in T‐lymphocyte migration , 2007, Immunological reviews.

[26]  Jason S. Mitchell,et al.  WAVE2 Regulates High-Affinity Integrin Binding by Recruiting Vinculin and Talin to the Immunological Synapse , 2007, Molecular and Cellular Biology.

[27]  D. Golan,et al.  Cytoskeletal regulation couples LFA-1 conformational changes to receptor lateral mobility and clustering. , 2006, Immunity.

[28]  P. Cullen,et al.  Sorting nexins , 2005, Current Biology.

[29]  K. Katagiri,et al.  Regulation of immune cell adhesion and migration by regulator of adhesion and cell polarization enriched in lymphoid tissues , 2005, Immunology.

[30]  Wenyan Lu,et al.  Sorting nexin 17 facilitates LRP recycling in the early endosome , 2005, The EMBO journal.

[31]  E. Palmer,et al.  The CD3ε Proline-Rich Sequence, and Its Interaction with Nck, Is Not Required for T Cell Development and Function1 , 2005, The Journal of Immunology.

[32]  Heidi Hahn,et al.  Functions of sorting nexin 17 domains and recognition motif for P-selectin trafficking. , 2005, Journal of molecular biology.

[33]  E. Palmer,et al.  The CD3epsilon proline-rich sequence, and its interaction with Nck, is not required for T cell development and function. , 2005, Journal of immunology.

[34]  T. Galli,et al.  [Activation-induced polarized recycling targets T cell receptors to the immunological synapse]. , 2005, Medecine sciences : M/S.

[35]  B. Nal,et al.  Activation-induced polarized recycling targets T cell antigen receptors to the immunological synapse; involvement of SNARE complexes. , 2004, Immunity.

[36]  A. Soutar,et al.  Sorting Motifs in the Intracellular Domain of the Low Density Lipoprotein Receptor Interact with a Novel Domain of Sorting Nexin-17* , 2004, Journal of Biological Chemistry.

[37]  Michael Loran Dustin,et al.  Membranes as messengers in T cell adhesion signaling , 2004, Nature Immunology.

[38]  Arup K Chakraborty,et al.  The Immunological Synapse Balances T Cell Receptor Signaling and Degradation , 2003, Science.

[39]  Jack E. Dixon,et al.  Sorting out the cellular functions of sorting nexins , 2003, Nature Reviews Molecular Cell Biology.

[40]  W. Schneider,et al.  The PX‐domain protein SNX17 interacts with members of the LDL receptor family and modulates endocytosis of the LDL receptor , 2002, The EMBO journal.

[41]  Balbino Alarcón,et al.  Recruitment of Nck by CD3ϵ Reveals a Ligand-Induced Conformational Change Essential for T Cell Receptor Signaling and Synapse Formation , 2002, Cell.

[42]  D. Wiest,et al.  On the dynamics of TCR:CD3 complex cell surface expression and downmodulation. , 2000, Immunity.

[43]  S. Bromley,et al.  The immunological synapse: a molecular machine controlling T cell activation. , 1999, Science.

[44]  Colin R. F. Monks,et al.  Three-dimensional segregation of supramolecular activation clusters in T cells , 1998, Nature.

[45]  T. Theander,et al.  The relation between T-cell expression of LFA-1 and immunological memory. , 1993, Immunology.