A synaptic scaffold quiets T cells

杨柳

A scaffolding protein at neuronal synapses has found its way to another kind of synapse—the immune synapse, which forms at the interface between antigen presenting cells and T cells. As shown by Xavier et al. on page 173, this multidomain protein, called Dlg1, tempers the activity of both types of synapses., Q( r- ^( K1 q3 I
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On the T cell side of the immune synapse, activated T cell antigen receptors (TCRs) congregate with many cytoskeletal and signaling molecules that spread the word of antigen recognition to the rest of the cell. Recognition of TCR engagement must be transmitted somehow to these other proteins to coordinate their synaptic congregation.
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( z6 P1 f  R8 E& l) T( c! W! MBased on its multidomain structure and role as a scaffold in neuronal synapses and epithelial junctions, Dlg1 seemed a likely candidate for this coordination job in T cells. The authors' localization data support this idea—Dlg1 moves from the cytosol to cortical actin at the immune synapse within five minutes of antigen recognition. There, Dlg is complexed with proteins needed for T cell activation, including a Src kinase, a TCR subunit, and the Cbl ubiquitin ligase, suggesting that it might bring these and perhaps other signaling proteins to the synapse.Once the complex has assembled, however, Dlg1's job seems to be to prevent overactivity of T cells, which could potentially cause autoimmune problems. Dlg1 overexpression limited T cell activation, whereas loss of Dlg1 caused an overactive response to antigen.% N1 l; n/ Y' l4 N0 [0 K
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In flies, Dlg1-like proteins both bring AMPA receptors to synapses and promote their degradation, which requires AMPA ubiquitination. Dlg1 might similarly cause immune receptor down-regulation, possibly via its interaction with Cbl. However, as Dlg1 left synapses within 15 min of TCR engagement, it might instead down-regulate T cell signaling by taking some other synaptic components with it.(Dlg1 (green) is at the immune synapse wi)