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| NF-κB activation: Rel-ative contribution of MALT1 and Bcl-10
The scaffold proteins MALT1 and Bcl-10 couple B-cell receptor signaling to NF-κB function through selective activation of the NF-κB subunit c-Rel. The heterodimeric transcription factor NF-κB consists of a regulatory subunit and a transcriptionally active RelA, RelB or c-Rel subunit. In unstimulated cells, each dimer is held in an inactive cytoplasmic complex by the inhibitory IκB protein. Activation of the B cell receptor (BCR) promotes IκB kinase (IKK)-mediated phosphorylation and degradation of IκB, which facilitates the nuclear translocation of NF-κB and transactivation of its target genes. In B cells, BCR-mediated NF-κB activation is coordinated through the formation of lipid raft signalosomes that contain the scaffold protein Bcl-10, the paracaspase scaffold MALT1, and IKK. However, the biological mechanisms that underlie signalosome formation and activation of NF-κB remain unclear. In Nature Immunology, Ferch et al. show that Bcl-10 and MALT1 have complementary yet distinct roles in promoting nuclear accumulation of the p50/c-Rel NF-κB dimer.
Mature B lymphocytes derived from Bcl10 and MALT1 knockout mice were used to evaluate their respective contributions to BCR signaling. Examination of the composition of signalosomes in the B cells revealed that MALT1 was not recruited to lipid rafts in BCR-stimulated Bcl10-/- cells, suggesting that Bcl-10 functions upstream of MALT1 and is important for its localization and activity. IKK and IκB were also missing from the lipid rafts in stimulated Bcl10-/- cells, and IKK remained inactive. Consequently, BCR signaling in Bcl10-/- cells failed to induce IκB degradation. Therefore, Bcl-10 appears to regulate BCR-mediated NF-κB signaling by promoting formation of an active signalosome. Activated IKK promotes the degradation of IκB and release of bound NF-κB in wild-type B cells. BCR signaling in Bcl10-/- cells failed to induce IκB degradation, consistent with the finding that IKK was not activated in these cells. Although IκB was degraded in MALT1-/- cells, BCR activation caused RelA, but not c-Rel accumulation in the nuclei of MALT1-/- cells. This differential accumulation was due to the persistence of IκB/c-Rel dimers in MALT1-/- cells, suggesting that MALT1 normally couples BCR signaling to c-Rel activation through targeted degradation of IκB in c-Rel-containing dimers. The authors propose a model of NF-κB activation in B cells in which BCR signaling recruits Bcl-10 to lipid rafts, where it promotes formation of a signalosome containing MALT1, IKK and IκB/NF-κB dimers. MALT1 then specifically promotes degradation of the IκB/NF-κB dimers that contain c-Rel, resulting in the transactivation of NF-κB target genes. Interestingly, mutations in c-Rel, but not RelA have been detected in human cancers, indicating that preferential BCR-mediated activation of c-Rel in B cells may have dramatic biological consequences. Whether this pathway is conserved in other settings of NF-κB signaling awaits future study. Emily J. Chenette
Reference
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