T-Cell Receptor-Induced NF-κB Activation Is Negatively Regulated by E3 Ubiquitin Ligase Cbl-b▿

摘要

It has previously been shown that E3 ubiquitin ligase Casitas B-lineage lymphoma-b (Cbl-b) negatively regulates T-cell activation, but the molecular mechanism(s) underlying this inhibition is not completely defined. In this study, we report that the loss of Cbl-b selectively results in aberrant activation of NF-κB upon T-cell antigen receptor (TCR) ligation, which is mediated by phosphatidylinositol 3-kinase (PI3-K)/Akt and protein kinase C-θ (PKC-θ). TCR-induced hyperactivation of Akt in the absence of Cbl-b may potentiate the formation of caspase recruitment domain-containing membrane-associated guanylate kinase protein 1 (CARMA1)-B-cell lymphoma/leukemia 10 (Bcl10)-mucosa-associated lymphatic tissue 1(MALT1) (CBM) complex, which appears to be independent of PKC-θ. Cbl-b associates with PKC-θ upon TCR stimulation and regulates TCR-induced PKC-θ activation via Vav-1, which couples PKC-θ to PI3-K and allows it to be phosphorylated. PKC-θ then couples IκB kinases (IKKs) to the CBM complex, resulting in the activation of the IKK complex. Therefore, our data provide the first evidence to demonstrate that the down-regulation of TCR-induced NF-κB activation by Cbl-b is mediated coordinately by both Akt-dependent and PKC-θ-dependent signaling pathways in primary T cells.