The dynamic distribution of CARD11 at the immunological synapse is regulated by the inhibitory kinesin GAKIN.

T cell receptor (TCR) signaling to NF-κB is required for antigen-induced T cell activation. We conducted an expression-cloning screen for modifiers of CARD11, a critical adaptor in antigen receptor signaling, and identified the kinesin-3 family member GAKIN as a CARD11 inhibitor. GAKIN negatively regulates TCR signaling to NF-κB, associates with CARD11 in a signal-dependent manner and can compete with the required signaling protein, Bcl10, for association. In addition, GAKIN dynamically localizes to the immunological synapse and regulates the redistribution of CARD11 from the central region of the synapse to a distal region. We propose that CARD11 scaffold function and occupancy at the center of the synapse are negatively regulated by GAKIN to tune the output of antigen-receptor signaling.