Another Adaptor in the T Cell Receptor Orchestra: CARMA1

Abstract

Two groups report the importance of a membrane-associated guanylate like kinase (MAGUK) domain-containing protein (CARMA1) in the activation of the transcription factor NF-κB in response to T cell receptor (TCR) ligation. Wang et al. isolated CARMA1 in a somatic mutagenesis screen of T cell lines with a selective defect in NF-κB signaling. Expression of activated protein kinase c θ (PKC θ), the adaptor Bcl10, or the MALTI protein did not restore NF-κB signaling. Expression of CARMA1, which is an adaptor protein and has a caspase recruitment domain (CARD), a PDZ domain, an SH3 domain, and the guanlyate kinase-like domain, restored NF-κB signaling. Coexpression experiments in human embryonic kidney (HEK 293) cells with various combinations of CARMA1, PKC θ, and BCL10 suggested that CARMA1 may serve to promote the PCK θ -induced phosphorylation of Bcl10. Gaide et al. determined that, in T cells, a population of CARMA1 was constitutively associated with detergent-insoluble domains, called lipid rafts, and that the interaction between CARMA1 and the TCR and CARMA1 and Bcl10 was stimulated upon TCR ligation. A mutant version of CARMA1 that could not interact with Bcl10 selectively inhibited TCR-stimulated NF-κB signaling in T cells. The results from these two groups suggest that CARMA1 may serve as a selective adaptor to specifically direct the activated TCR signal to NF-κB. The potential therapeutic importance of these results for the development of immunosuppressive drugs is discussed by Wallach. D. Wang, Y. You, S. M. Case, L. M. McAllister-Lucas, L. Wang, P. S. DiStefano, G. Nuñez, J. Bertin, X. Lin, A requirement for CARMA1 in TCR-induced NF-κB activation. Nature Immunol. 3, 830-835 (2002). [Online Journal]O. Gaide, B. Favier, D. F. Legler, D. Bonnet, B. Brissoni, S. Valitutti, C. Bron, J. Tschopp, M. Thome, CARMA1 is a critical lipid raft-associated regulator of TCR-induced NF-κB activation. Nature Immunol. 3, 836-843 (2002). [Online Journal]D. Wallach, Up the down staircase. Nature Immunol. 3, 802-803 (2002). [Online Journal]