Breaking T Cell Activation by IKKbeta
We have published that IKKβ phosphorylates Bcl10 on a different site [Wegener et al., Mol Cell 23, 13-23 (2006)]. We have identified five serine residues in the C-terminus of Bcl10 (Ser 134, 136, 138, 141, 144) that are phosphorylated by IKKβ. In our analysis, we found no evidence that IKKβ triggers Bcl10 degradation using IKKβ inhibitors and IKKβ-deficient T cells. Instead, C-terminal phosphorylation of Bcl10 promotes dissociation of Bcl10-MALT1 complexes. To address the physiological consequences, we rescued T cells from BCL10-deficient mice by retroviral infection using wild-type and mutant Bcl10 (S134, 136, 138, 141, 144A) constructs and showed that phosphorylation of the C-terminal sites induces a negative feedback mechanism. The experiments that we performed were done in the absence of endogenous Bcl10. In the case of Lobry et al., the prediction of a negative feedback mechanism is based on monitoring interleukin 2 (IL-2) production after overexpression of Bcl10 wild-type or mutant (T81A/S85A). There is no correlation that the mutation promotes prolonged T cell receptor signaling to NF-κB. In addition, they show an accumulation of mutant Bcl10 T81A/S85A in the nucleus. Even though it remains unresolved whether nuclear localization is linked to enhanced IL-2 expression, the Bcl10 T81A/S85A mutant described by Lobry et al. may also have a dominant effect on IL-2 production. Future studies are needed to determine the relevance of alternative Bcl10 phosphorylations under different physiological or pathological conditions.
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