Immunology
Turning NF-
B On and Off
Wei Wong
Science Signaling, AAAS, Washington, DC 20005, USA
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-
B (nuclear factor kappa B) by promoting the phosphorylation and degradation of IK (inhibitor of NF-B kinase), thereby allowing NF-B to translocate to the nucleus to activate gene transcription. Bidère et al. found that casein kinase 1
(CK1) 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 CK1 reduced interleukin-2 production and proliferation in primary human T cells, NF-B nuclear translocation after T cell receptor (TCR) stimulation in primary T cells and Jurkat cells, and NF-B activity as measured by a luciferase reporter in Jurkat cells. In Jurkat clones stably expressing a short hairpin RNA (shRNA) against CK1, NF-B activation, as well as IB phosphorylation and degradation, were reduced compared with clones expressing a control shRNA, and the effects of the CK1 shRNA were rescued by expression of ectopic mouse CK1 (mCK1) but not of a mCK1 mutant lacking the CARD11 binding site. However, expression of a kinase-dead version of mCK1 enhanced TCR-induced NF-B activation and IB phosphorylation and degradation, suggesting an inhibitory role for CK1 kinase activity in regulating NF-B activation. Accordingly, in CARD11-siRNA-transfected Jurkat cells, NF-B activity was enhanced by the expression of a CARD11 mutant that could not be phosphorylated by CK1 at Ser608 compared with wild-type CARD11. Thus, CK1 has dual roles in both promoting and limiting the activation of NF-B 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 1 governs antigen-receptor-induced NF-B activation and human lymphoma cell survival. Nature 458, 92–96 (2009). [PubMed]
