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NF-B activation pathways induced by T cell costimulation

M. LIENHARD SCHMITZ^*,1, SUSANNE BACHER^* and OLIVER DIENZ

^* University of Bern, Department of Chemistry and Biochemistry, CH-3012 Bern, Switzerland; and
Immunobiology Program, Department of Medicine, University of Vermont, Burlington, Vermont, USA

¹Correspondence: University of Bern, Department of Chemistry and Biochemistry, Freiestr. 3, CH-3012 Bern, Switzerland. E-mail: Lienhard.Schmitz{at}ibc.unibe.ch

Analysis of knockout mice and of T cells deficient for individual signaling proteins allowed the identification of novel members of the costimulation-induced NF-B activation pathway while biochemical approaches started to unveil their functional mechanisms. These results show that NF-B activation depends on an early wave of tyrosine phosphorylation that allows the inducible formation of multiprotein complexes containing several proteins required for NF-B activation: adaptor proteins including Src homology 2 domain-containing leukocyte phosphoprotein 76 (SLP-76) and proteins with enzymatic activity, such as phospholipase C (PLC) and the exchange factor Vav1. While Vav1 contributes to Rac-dependent reorganization of the actin cytoskeleton, activated PLC1 generates the protein kinase C (PKC) activator diacylglycerol. In T cells, the novel PKC isoform PKC is indispensable for NF-B activation and its enzymatic activity depends on recruitment to the immunological synapse. Downstream from PKC, the caspase recruitment domain (CARD) proteins CARD11/CARMA1 and Bcl10 relay T cell receptor-derived signals to the IB kinase (IKK) complex. Many members of the NF-B activation cascade, including the IKKs, are either constitutively or inducibly translocated to the lipid raft fraction, showing a highly organized spatial distribution of these NF-B activating proteins.—Schmitz, M. L., Bacher, S., Dienz, O. NF-B activation pathways induced by T cell costimulation.

Key Words: IKK • Vav • PKC

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