congresos y reuniones científicas
Biochemical analysis of T cell receptor pathways
St Jude Childrens Research hospital. Memphis, TN. USA.
Conferencia; Infectious Disease Research Conference; 2009
Institución organizadora:
St Jude Childrens Research hospital.
Activation through the T-cell receptor (TCR) leads to the initiation of multiple signaling cascades that regulate survival, cytokine production and proliferation of T-cells. A key event upon TCR engagement is the formation of a signaling complex between CARMA1, BCL10 and MALT1, referred to as CBM complex. These three molecules interact physically and functionally. The components of this complex were found to be essential for T-cell activation, in particular by controlling the NF-kB and MAP kinase signal transduction pathways. Therefore, within the CBM complex, experimental data suggest that the adaptor protein BCL10 play a key role by providing a molecular link between CARMA1 and MALT1. It has been uncertain whether other additional molecules that exist in these signaling pathways are involved, because of the lack of appropriate techniques for the analysis of activated signaling complexes in living cells.  We have successfully identified a novel NF-kB activating protein as part of the BCL10 complex by using BCL10 as bait and the semi-quantitative MS method as analysis tool. This novel-BCL10 interacting-protein is constitutively associated with BCL10 at low levels and significantly recruited upon activation. Overexpression of this protein leads to a strong increase in transcriptional NF-kB activity, indicating that this ?novel BCL10-interacting protein? that we have found represents a missing link in the TCR-/ BCL10-dependent NF-kB activation pathway. In addition, we also found MALT1 to be constitutively associated to the BCL-10 complex. Besides, we have characterized the molecular mechanism of the novel protein-dependent NF-kB activation and identified the structural domains of the novel protein that control BCL10 interaction and effector functions. Identification of the molecular events of the CBM complex will further our understanding of T-cell activation, a critical event not just in the defense against pathogens, but also critically involved in the initiation and progression of inflammatory diseases such as allergy and asthma or autoimmunity.