Essential Role for IκB Kinase β in Remodeling Carma1-Bcl10-Malt1 Complexes upon T Cell Activation

Abstract

T cell receptor (TCR) signaling to IκB kinase (IKK)/NF-κB is controlled by PKCθ-dependent activation of the Carma1, Bcl10, and Malt1 (CBM) complex. Antigen-induced phosphorylation of Bcl10 has been reported, but its physiological function is unknown. Here we show that the putative downstream kinase IKKβ is required for initial CBM complex formation. Further, upon engagement of IKKβ/Malt1/Bcl10 with Carma1, IKKβ phosphorylates Bcl10 in the C terminus and thereby interferes with Bcl10/Malt1 association and Bcl10-mediated IKKγ ubiquitination. Mutation of the IKKβ phosphorylation sites on Bcl10 enhances expression of NF-κB target genes IL-2 and TNFα after activation of primary T cells. Thus, our data provide evidence that IKKβ serves a dual role upstream of its classical substrates, the IκB proteins. While being essential for triggering initial CBM complex formation, IKKβ-dependent phosphorylation of Bcl10 exhibits a negative regulatory role in T cell activation. © 2006 Elsevier Inc. All rights reserved.