title: Rab11-FIP3 Regulation of Lck Endosomal Traffic Controls TCR Signal Transduction.
abstract: The role of endosomes in receptor signal transduction is a long-standing question, which remains largely unanswered. The T cell Ag receptor and various components of its proximal signaling machinery are associated with distinct endosomal compartments, but how endosomal traffic affects T cell signaling remains ill-defined. In this article, we demonstrate in human T cells that the subcellular localization and function of the protein tyrosine kinase Lck depends on the Rab11 effector FIP3 (Rab11 family interacting protein-3). FIP3 overexpression or silencing and its ability to interact with Rab11 modify Lck subcellular localization and its delivery to the immunological synapse. Importantly, FIP3-dependent Lck localization controls early TCR signaling events, such as tyrosine phosphorylation of TCRζ, ZAP70, and LAT and intracellular calcium concentration, as well as IL-2 gene expression. Interestingly, FIP3 controls both steady-state and poststimulation phosphotyrosine and calcium levels. Finally, our findings indicate that FIP3 modulates TCR-CD3 cell surface expression via the regulation of steady-state Lck-mediated TCRζ phosphorylation, which in turn controls TCRζ protein levels. This may influence long-term T cell activation in response to TCR-CD3 stimulation. Therefore, our data underscore the importance of finely regulated endosomal traffic in TCR signal transduction and T cell activation leading to IL-2 production.
authors.affiliation: Department of Immunology, Lymphocyte Cell Biology Unit, Institut Pasteur, 75724 Paris, France; andres.alcover@pasteur.fr jerome.bouchet@inserm.fr.|CNRS URA1961, 75724 Paris Cedex 15, France.|INSERM U1221, 75724 Paris Cedex 15, France; and.
authors.forename: Jérôme
authors.identifier: 0000-0002-6611-4380
authors.initials: J
authors.lastname: Bouchet
authors.affiliation: Department of Immunology, Lymphocyte Cell Biology Unit, Institut Pasteur, 75724 Paris, France.|CNRS URA1961, 75724 Paris Cedex 15, France.|INSERM U1221, 75724 Paris Cedex 15, France; and.
authors.forename: Iratxe
authors.initials: I
authors.lastname: Del Río-Iñiguez
authors.affiliation: Department of Immunology, Lymphocyte Cell Biology Unit, Institut Pasteur, 75724 Paris, France.|CNRS URA1961, 75724 Paris Cedex 15, France.|INSERM U1221, 75724 Paris Cedex 15, France; and.
authors.forename: Elena
authors.identifier: 0000-0002-9461-1608
authors.initials: E
authors.lastname: Vázquez-Chávez
authors.affiliation: Department of Immunology, Lymphocyte Cell Biology Unit, Institut Pasteur, 75724 Paris, France.|CNRS URA1961, 75724 Paris Cedex 15, France.
authors.forename: Rémi
authors.initials: R
authors.lastname: Lasserre
authors.affiliation: Department of Immunology, Lymphocyte Cell Biology Unit, Institut Pasteur, 75724 Paris, France.|CNRS URA1961, 75724 Paris Cedex 15, France.
authors.forename: Sonia
authors.initials: S
authors.lastname: Agüera-González
authors.affiliation: Department of Immunology, Lymphocyte Cell Biology Unit, Institut Pasteur, 75724 Paris, France.|CNRS URA1961, 75724 Paris Cedex 15, France.|INSERM U1221, 75724 Paris Cedex 15, France; and.
authors.forename: Céline
authors.initials: C
authors.lastname: Cuche
authors.affiliation: Molecular Cell Biology Laboratory, School of Biochemistry and Cell Biology, Biosciences Institute, University College Cork, Cork, Ireland.
authors.forename: Mary W
authors.initials: MW
authors.lastname: McCaffrey
authors.affiliation: Department of Immunology, Lymphocyte Cell Biology Unit, Institut Pasteur, 75724 Paris, France.|CNRS URA1961, 75724 Paris Cedex 15, France.|INSERM U1221, 75724 Paris Cedex 15, France; and.
authors.forename: Vincenzo
authors.identifier: 0000-0002-5453-947X
authors.initials: V
authors.lastname: Di Bartolo
authors.affiliation: Department of Immunology, Lymphocyte Cell Biology Unit, Institut Pasteur, 75724 Paris, France; andres.alcover@pasteur.fr jerome.bouchet@inserm.fr.|CNRS URA1961, 75724 Paris Cedex 15, France.|INSERM U1221, 75724 Paris Cedex 15, France; and.
authors.forename: Andrés
authors.identifier: 0000-0002-9507-3450
authors.initials: A
authors.lastname: Alcover
mesh_terms: D015153:Blotting, Western; D011992:Endosomes / Q000276:immunology; D055785:Gene Knockdown Techniques; D006801:Humans; D051550:I-kappa B Kinase / Q000276:immunology; D054992:Immunological Synapses / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000276:immunology; D018613:Microscopy, Confocal; D016133:Polymerase Chain Reaction; D021381:Protein Transport / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D020691:rab GTP-Binding Proteins / Q000276:immunology; D000099193:rab11 GTP-Binding Proteins
chemical_list: D051550:I-kappa B Kinase; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D011948:Receptors, Antigen, T-Cell; D020691:rab GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins; C491731:IKBKG protein, human