title: Rab8 binding to immune cell-specific adaptor LAX facilitates formation of trans-Golgi network-proximal CTLA-4 vesicles for surface expression.
abstract: Despite playing a central role in tolerance, little is known regarding the mechanism by which intracellular CTLA-4 is shuttled from the trans-Golgi network to the surfaces of T cells. In this context, Ras-related GTPase Rab8 plays an important role in the intracellular transport, while we have previously shown that CTLA-4 binds to the immune cell adaptor TRIM in T cells. In this study, we demonstrate that CTLA-4 forms a multimeric complex comprised of TRIM and related LAX that in turn binds to GTP bound Rab8 for post-Golgi transport to the cell surface. LAX bound via its N terminus to active GTP-Rab8, as well as the cytoplasmic tail of CTLA-4. TRIM required LAX for binding to Rab8 in a complex. Wild-type LAX or its N terminus (residues 1 to 77) increased CTLA-4 surface expression, whereas small interfering RNAs of Rab8 or LAX or disruption of LAX/Rab8 binding reduced numbers of CTLA-4-containing vesicles and its coreceptor surface expression. LAX also promoted the polarization of CTLA-4 and the reorientation of the microtubule-organizing center to the site of T-cell receptor engagement. Our results identify a novel CTLA-4/TRIM/LAX/Rab8 effector complex in the transport of CTLA-4 to the surfaces of T cells.
authors: Cell Signalling Section, Division of Immunology, Department of Pathology, Cambridge University, Cambridge, United Kingdom.
authors: Matthew C
authors: MC
authors: Banton
authors: Kerry L
authors: KL
authors: Inder
authors: Elke
authors: E
authors: Valk
authors: Christopher E
authors: CE
authors: Rudd
authors: Helga
authors: H
authors: Schneider
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D060908:CTLA-4 Antigen / Q000276:immunology / Q000378:metabolism*; D018929:Cell Culture Techniques; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D000081410:Germinal Center Kinases; D006801:Humans; D051379:Mice; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000276:immunology / Q000378:metabolism*; D021381:Protein Transport / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D021601:trans-Golgi Network / Q000378:metabolism*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D060908:CTLA-4 Antigen; D000081410:Germinal Center Kinases; C469997:LAX1 protein, human; D011948:Receptors, Antigen, T-Cell; D017346:Protein Serine-Threonine Kinases; D020559:Monomeric GTP-Binding Proteins