Editors' ChoiceImmunology

Turning NF-κB On and Off

Science Signaling  10 Mar 2009:
Vol. 2, Issue 61, pp. ec91
DOI: 10.1126/scisignal.261ec91

In lymphocytes, antigen receptor stimulation triggers the assembly of a complex containing the caspase recruitment domain (CARD)–containing scaffold protein CARD11, BCL10 (B cell chronic lymphocytic leukemia or lymphoma 10), and MALT1 (mucosa-associated lymphoid tissue 1). This CBM complex activates the transcription factor NF-κB (nuclear factor kappa B) by promoting the phosphorylation and degradation of IκK (inhibitor of NF-κB kinase), thereby allowing NF-κB to translocate to the nucleus to activate gene transcription. Bidère et al. found that casein kinase 1α (CK1α) directly associated through its C-terminal domain with CARD11 and was recruited to the CBM complex in stimulated Jurkat T lymphocytes and BJAB B cells. Small interfering RNA (siRNA) knockdown of CK1α reduced interleukin-2 production and proliferation in primary human T cells, NF-κB nuclear translocation after T cell receptor (TCR) stimulation in primary T cells and Jurkat cells, and NF-κB activity as measured by a luciferase reporter in Jurkat cells. In Jurkat clones stably expressing a short hairpin RNA (shRNA) against CK1α, NF-κB activation, as well as IκBα phosphorylation and degradation, were reduced compared with clones expressing a control shRNA, and the effects of the CK1α shRNA were rescued by expression of ectopic mouse CK1α (mCK1α) but not of a mCK1α mutant lacking the CARD11 binding site. However, expression of a kinase-dead version of mCK1α enhanced TCR-induced NF-κB activation and IκBα phosphorylation and degradation, suggesting an inhibitory role for CK1α kinase activity in regulating NF-κB activation. Accordingly, in CARD11-siRNA-transfected Jurkat cells, NF-κB activity was enhanced by the expression of a CARD11 mutant that could not be phosphorylated by CK1α at Ser608 compared with wild-type CARD11. Thus, CK1α has dual roles in both promoting and limiting the activation of NF-κB through the CBM complex.

N. Bidère, V. N. Ngo, J. Lee, C. Collins, L. Zheng, F. Wan, R. E. Davis, G. Lenz, D. E. Anderson, D. Arnoult, A. Vazquez, K. Sakai, J. Zhang, Z. Meng, T. D. Veenstra, L. M. Staudt, M. J. Lenardo, Casein kinase 1α governs antigen-receptor-induced NF-κB activation and human lymphoma cell survival. Nature 458, 92–96 (2009). [PubMed]