Valk Elke, Leung Rufina, Kang Hyun, Kaneko Kazuyo, Rudd Christopher E, Schneider Helga
Cell Signalling Section, Division of Immunology, Department of Pathology, Cambridge University, Cambridge, UK.
Immunity. 2006 Nov;25(5):807-21. doi: 10.1016/j.immuni.2006.08.024. Epub 2006 Oct 26.
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.
共刺激分子CTLA-4是T细胞反应的有效下调因子。尽管它主要定位于细胞内区室，但关于调节其转运至细胞表面的机制仍知之甚少。在本研究中，我们证明衔接蛋白TRIM（T细胞受体相互作用分子）在反式高尔基体网络（TGN）中与CTLA-4结合，并促进CTLA-4转运至T细胞表面。TRIM表达增加会增强表面CTLA-4的表达，脉冲追踪分析表明CTLA-4向细胞表面的转运更快。通过小发夹RNA降低TRIM表达会减少表面CTLA-4的表达。这导致CTLA-4在TGN中的分布模式更加局限。TRIM改变CTLA-4表达的同时，共受体介导的对细胞因子产生和增殖的影响也会发生相应变化。我们的研究结果确定了TRIM作为伴侣蛋白的作用，即通过增强CTLA-4向T细胞表面的转运来调节CTLA-4的表达和功能。
