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T-cell-receptor (TCR) signalling to NFκB requires the assembly of a large multiprotein complex containing the serine/threonine kinase CK1α, the scaffold protein CARMA1, the heterodimer BCL10-MALT1 (the CBM complex) and the IκB 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 IκBα, the inhibitor of NFκB, to promote IκBα ubiquitylation and proteasomal degradation. Here, we show that BCL10, MALT1 and IKK inducibly associate with IκBα in a complex that is physically distinct from the early CK1α-CBM signalosome. This IκBα-containing complex probably maturates from the CBM, because siRNA-based knockdown of CARMA1, CK1α and BCL10 hampered its assembly, leading to a reduction in NFκB activation. By contrast, CK1α normally recruited both BCL10 and ubiquitylated species of MALT1 when IκBα levels were reduced. However, knockdown of IκBα led to an altered ubiquitylation profile of BCL10-MALT1 combined with a defect in MALT1 reorganisation within large cytoplasmic structures, suggesting that, following stimulation, IκBα might also participate in MALT1 recycling. Altogether, our data suggest a two-step mechanism to connect active IKK to IκBα, and further unveil a potential role for IκBα in resetting TCR-mediated signalling.

  • Accepted April 23, 2010.
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