Interplay between BCL10, MALT1 and IκBα during T-cell-receptor-mediated NFκB activation

T-cell-receptor (TCR) signalling to NF kappa B requires the assembly of a large multiprotein complex containing the serine/threonine kinase CK1 alpha, the scaffold protein CARMA1, the heterodimer BCL10-MALT1 (the CBM complex) and the I kappa B kinase complex (IKK). Although the mechanisms regulating recruitment and activation of IKK within the CBM microenvironment have been extensively studied, there is little understanding of how IKK subsequently binds and phosphorylates I kappa B alpha, the inhibitor of NF kappa B, to promote I kappa B alpha ubiquitylation and proteasomal degradation. Here, we show that BCL10, MALT1 and IKK inducibly associate with I kappa B alpha in a complex that is physically distinct from the early CK1 alpha-CBM signalosome. This I kappa B alpha-containing complex probably maturates from the CBM, because siRNA-based knockdown of CARMA1, CK1 alpha and BCL10 hampered its assembly, leading to a reduction in NF kappa B activation. By contrast, CK1 alpha normally recruited both BCL10 and ubiquitylated species of MALT1 when I kappa B alpha levels were reduced. However, knockdown of I kappa B alpha led to an altered ubiquitylation profile of BCL10-MALT1 combined with a defect in MALT1 reorganisation within large cytoplasmic structures, suggesting that, following stimulation, I kappa B alpha might also participate in MALT1 recycling. Altogether, our data suggest a two-step mechanism to connect active IKK to I kappa B alpha, and further unveil a potential role for I kappa B alpha in resetting TCR-mediated signalling.