T cell receptor-interacting molecule acts as a chaperone to modulate surface expression of the CTLA-4 coreceptor.
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.
Valk
Elke
E
Cell Signalling Section, Division of Immunology, Department of Pathology, Cambridge University, Cambridge, UK.
Leung
Rufina
R
Kang
Hyun
H
Kaneko
Kazuyo
K
Rudd
Christopher E
CE
Schneider
Helga
H
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
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