title: T cell receptor-interacting molecule acts as a chaperone to modulate surface expression of the CTLA-4 coreceptor.
abstract: The costimulatory molecule CTLA-4 is a potent downregulator of T cell responses. Although localized mostly in intracellular compartments, little is understood regarding the mechanism that regulates its transport to the cell surface. In this study, we demonstrated that the adaptor TRIM (T cell receptor-interacting molecule) bound to CTLA-4 in the trans Golgi network (TGN) and promoted transport of CTLA-4 to the surface of T cells. Increased TRIM expression augmented surface CTLA-4 expression, and pulse-chase analysis showed a more rapid transport of CTLA-4 to the cell surface. A reduction of TRIM expression by small hairpin RNAs reduced the expression of surface CTLA-4. This resulted in a more localized pattern of CTLA-4 in the TGN. Altered CTLA-4 expression by TRIM was accompanied by corresponding changes in coreceptor-mediated effects on cytokine production and proliferation. Our findings identify a role for TRIM as a chaperone in regulating CTLA-4 expression and function by enhancing CTLA-4 transport to the surface of T cells.
authors.affiliation: Cell Signalling Section, Division of Immunology, Department of Pathology, Cambridge University, Cambridge, UK.
authors.forename: Elke
authors.initials: E
authors.lastname: Valk
authors.forename: Rufina
authors.initials: R
authors.lastname: Leung
authors.forename: Hyun
authors.initials: H
authors.lastname: Kang
authors.forename: Kazuyo
authors.initials: K
authors.lastname: Kaneko
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Rudd
authors.forename: Helga
authors.initials: H
authors.lastname: Schneider
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D015703:Antigens, CD / Q000378:metabolism*; D000943:Antigens, Differentiation / Q000378:metabolism*; D017252:CD3 Complex / Q000378:metabolism; D060908:CTLA-4 Antigen; D002462:Cell Membrane / Q000378:metabolism*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D008213:Lymphocyte Activation / Q000502:physiology; D008565:Membrane Proteins / Q000378:metabolism*; D018832:Molecular Chaperones / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism* / Q000648:ultrastructure; D014162:Transfection; D021601:trans-Golgi Network / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; D000943:Antigens, Differentiation; D017252:CD3 Complex; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D008565:Membrane Proteins; D018832:Molecular Chaperones; D011948:Receptors, Antigen, T-Cell; C114030:TRAT1 protein, human