title: β-Arrestin-1 mediates the TCR-triggered re-routing of distal receptors to the immunological synapse by a PKC-mediated mechanism.
abstract: T-cell receptors (TCR) recognize their antigen ligand at the interface between T cells and antigen-presenting cells, known as the immunological synapse (IS). The IS provides a means of sustaining the TCR signal which requires the continual supply of new TCRs. These are endocytosed and redirected from distal membrane locations to the IS. In our search for novel cytoplasmic effectors, we have identified β-arrestin-1 as a ligand of non-phosphorylated resting TCRs. Using dominant-negative and knockdown approaches we demonstrate that β-arrestin-1 is required for the internalization and downregulation of non-engaged bystander TCRs. Furthermore, TCR triggering provokes the β-arrestin-1-mediated downregulation of the G-protein coupled chemokine receptor CXCR4, but not of other control receptors. We demonstrate that β-arrestin-1 recruitment to the TCR, and bystander TCR and CXCR4 downregulation, are mechanistically mediated by the TCR-triggered PKC-mediated phosphorylation of β-arrestin-1 at Ser163. This mechanism allows the first triggered TCRs to deliver a stop migration signal, and to promote the internalization of distal TCRs and CXCR4 and their translocation to the IS. This receptor crosstalk mechanism is critical to sustain the TCR signal.
authors: Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, Madrid, Spain.
authors: Elena
authors: E
authors: Fernández-Arenas
authors: Enrique
authors: E
authors: Calleja
authors: Nadia
authors: N
authors: Martínez-Martín
authors: Severine I
authors: SI
authors: Gharbi
authors: Rosana
authors: R
authors: Navajas
authors: Noel
authors: N
authors: García-Medel
authors: Petronila
authors: P
authors: Penela
authors: Antonio
authors: A
authors: Alcamí
authors: Federico
authors: F
authors: Mayor
authors: Juan P
authors: JP
authors: Albar
authors: Balbino
authors: B
authors: Alarcón
mesh_terms: D000818:Animals; D019390:Arrestins / Q000378:metabolism*; D015153:Blotting, Western; D018274:Electroporation; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation / Q000276:immunology*; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D054992:Immunological Synapses / Q000378:metabolism*; D047468:Immunoprecipitation; D019169:Jurkat Cells; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D018448:Models, Immunological; D011743:Pyrimidines; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D059008:Time-Lapse Imaging; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins
chemical_list: C412373:AG 1879; C000605253:ARRB1 protein, human; C000605255:Arrb1 protein, mouse; D019390:Arrestins; D011743:Pyrimidines; D011948:Receptors, Antigen, T-Cell; D019718:Receptors, CXCR4; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins