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

Sections of Nephrology,¹ Rheumatology, Department of Medicine,² Committee on Immunology, The University of Chicago, 5841 S. Maryland Ave., Chicago, Illinois 60637,³ Department of Microbiology and Immunology, University of Illinois at Chicago, 835 S. Wolcott, Chicago, Chicago, Illinois 60612,⁴ Institute of Molecular Biotechnology, The Austrian Academy of Sciences, 1030 Vienna, Austria⁵

Received 18 August 2007/ Returned for modification 24 September 2007/ Accepted 17 January 2008

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-B upon T-cell antigen receptor (TCR) ligation, which is mediated by phosphatidylinositol 3-kinase (PI3-K)/Akt and protein kinase C- (PKC-). 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-. Cbl-b associates with PKC- upon TCR stimulation and regulates TCR-induced PKC- activation via Vav-1, which couples PKC- to PI3-K and allows it to be phosphorylated. PKC- then couples IB 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-B activation by Cbl-b is mediated coordinately by both Akt-dependent and PKC--dependent signaling pathways in primary T cells.

Published ahead of print on 28 January 2008.